NATIONAL INSTITUTES OF HEALTH • OFFICE OF THE DIRECTOR | VOLUME 28 ISSUE 3 • MAY-JUNE 2020
NIH and the 1918 Flu COVID-19 Timeline at NIH From Alice Evans’s Memoirs Highlights through April 30, 2020 BY ALICE EVANS (SEPTEMBER 2 1963) COMPILED BY LAURA STEPHENSON CARTER
The following is an excerpt from Alice Evans’s memoirs, written in 1963, about her experiences during the 1918 influenza pandemic. Evans Evans, a bacteriologist, was one of the first women scientists at NIH and worked there from 1918 to 1945. Her research led to the recognition of brucellosis as a public-health problem and the acceptance of the need to pasteurize milk.
Perhaps an account of how the influenza pandemic of 1918 affected CREDIT: ROCKY MOUNTAIN LABS, NIAID LABS, MOUNTAIN ROCKY CREDIT: one member of the staff of the Hygienic Laboratory [the forerunner to NIH] will give [people]…whose knowledge of such epidemics is gained by reading, fortunately not by experience, an idea of the disruption that a serious epidemic may cause. [The 1918 flu] struck Massachusetts in September and reached Washington [D.C.] in early October. Here war-time conditions favored a rapid spread of the disease, for the This scanning electron microscope image shows SARS-CoV-2 (yellow)—the virus that causes COVID-19—isolated from a patient in the United States. The virus is emerging from the surface of cells (blue and pink) cultured in the lab. The image city was over-filled with dislocated people, was captured and colorized at NIAID’s Rocky Mountain Laboratories in Hamilton, Montana. the majority of whom were women who had come to do the vastly increased war-time The COVID-19 pandemic has upended the way work is getting done at NIH work of the government departments. They these days. Thousands of NIHers are teleworking, and all labs have minimal staffing to were crowded in boarding houses with three carry on essential research or maintenance operations. But many NIH scientists have been or more persons commonly occupying one working around the clock trying to decipher the secrets held by the virus that causes the room as a result of the shortage of housing. disease and to develop treatments and vaccines. The NIH Catalyst has compiled a timeline When someone became ill and a threat to highlighting much of what is going on during this historic time (see page 11). associates, she was apt to find herself very CONTINUED ON PAGE 11 much alone, with no one to take care of her. Some landladies dismissed boarders coming CONTENTS down with the disease. FEATURES • |1, 11| COVID-19 Timeline at NIH |4| Frolicking Foxes |5| Rare Disease Day and the On October 1 [1918], Congress passed DADA2 Story |6,7| WALS: Nobel Laureates Frances Arnold and James Allison |12| Profile: Emily a resolution “to enable the Public Hea1th Chew |14| Profile: John Tisdale Service to combat [the 1918 flu] and other DEPARTMENTS • |1| NIH History: The 1918 Flu |2| DDIR: Working Together While Staying CONTINUED ON PAGE 10 Apart |3| SIG Beat: COVID-19 |4| Training: Medical Science Liaison |8| Research Briefs 16| Colleagues: Tenured |19| Abbreviations |20| Photographic Moment: Thank You Dr. Fauci! FROM THE DEPUTY DIRECTOR FOR INTRAMURAL RESEARCH
Working Together While Staying Apart Best Practices for “Virtual” Interactions BY MICHAEL GOTTESMAN, DDIR
All of us have been experiencing the issue, appear in person on video wherever anyone has a question or comment. If you isolation, anxiety, and frustrations of deal- possible. Visual cues and feedback, such as are building on someone else’s idea, be sure ing with the COVID-19 pandemic. For perplexed looks, raising your hand, or nods to give them credit. most of us this is a stressful period, yet we of agreement, can be important for meeting Say when you have finished talking so still must carry on our interactions with flow. Avoid the temptation to be too casual that others know it is their turn, particularly our colleagues, now physically separated in a videoconference for work. At least wear in large groups with no visual cues. I’ve heard from us, using communication tools that your good sweatshirt. Try to be on time for several people simply say “Over” like an air- may be unfamiliar and at times add addi- videoconferences. It is a sign that you respect line pilot when finished speaking—that is tional stress. It is especially important that the time of others and avoids embarrassing pretty clear and helpful. we continue to interact with each other in and disruptive beeps in the middle of some- A wise person once told me that the a civil and respectful manner. one speaking. Please mute your microphone difference between good people and great Most of you are now teleworking. people is what they do during their For some of you, it is just a matter down time. I have advised my lab staff of figuring out how to do your During videoconferences, and trainees to use this time to read regular job from home. For many scientific papers, take online courses, of our bench scientists and trainees, civility and decorum are just as update their CVs, design experiments, it is a matter of finding new ways important online, as they are in develop research plans, and write man- to contribute to the biomedical- uscripts. If you have not recently looked research enterprise. I am impressed person. at our list of Scientific Interest Groups with the professionalism that all of (SIGs), or other affinity groups, now is you have shown in adapting to this a good time to do so. These groups are (or phone) when you are not speaking. Use new normal. As the Deputy Director for great resources for networking, information a headset, if available, to reduce feedback Intramural Research and a lab chief in sharing, and finding out about career and and extraneous noise. When possible, have the National Cancer Institute’s Center for collaboration opportunities. Some of them an agenda and stick to it. There should also Cancer Research, I am simultaneously deal- continue to host seminars and other events be a clearly designated meeting moderator. ing with both sets of challenges. online. Recently created SIGs include one It is especially important during vid- In my administrative role, I have been devoted to COVID-19 research. eoconferences that only one person speak using multiple videoconferencing platforms In addition, teleworking time can be at a time. Some videoconferencing systems with varying amounts of success. That said, used to binge watch archived videocasts of automatically shift to the loudest voice. If I have observed a few promising practices lectures from the Wednesday Afternoon this is a regular meeting, you should decide, for small group meetings (less than 15 Lecture Series (WALS), Clinical Center as a group, the best way to ask a question. people), such as staff meetings, in which Grand Rounds, Demystifying Medicine, Options might include using the text or there would normally be a lot of back and and other lectures and conferences going chat feature in your videoconferencing tool forth discussion. Civility and decorum are back to 1993. Our Office of Intramural (highly recommended), using the raise-hand just as important online as they are in person. Training and Education (OITE) also con- feature, or actually raising your hand, if you In my experience, civility and respect are tinues to host online events on topics relevant are sharing your video. When speaking for practiced well at the NIH in the midst of to career development and wellness. an extended period, pause every few minutes this present crisis. Speaking of wellness, it is important to to check the text and chat messages and look If bandwidth and privacy are not an take care of yourselves. Try to build some at the people sharing their videos to see if
2 THE NIH CATALYST MAY-JUNE 2020 THE SIG BEAT NEWS FROM AND ABOUT THE SCIENTIFIC INTEREST GROUPS
NEW SIG: COVID-19 NIH and HHS, external scientists can view the archive of messages. For instruc- Scientific Interest tions, go to https://oir.nih.gov/sigs/ physical activity into each day. Have regular covid-19-scientific-interest-group. breaks from screen time. Also remember Group • Anyone can send messages to the list at that social distancing does not mean social [email protected]. isolation. Call friends or family just to say The COVID-19 Scientific Interest • HHS staff also can join the Microsoft hello and let each other know how you are Group was created in March 2020 in Teams group. Launch the Microsoft Teams doing. I know how much a call from one of response to the COVID-19 pandem- program, search for “OD COVID-19 Sci- my children or grandchildren means to me. ic. This interest group is intended for entific Interest Group,” and ask to join. Finally, if you need help, do not suffer NIH scientists and HHS colleagues to in silence. There are many other groups at exchange information concerning research Virtual Lecture Series: NIH (see list below) that are available to on COVID-19 disease and the virus that Wednesdays, 3:00–4:00 p.m. provide help with issues that might arise. causes it—severe acute respiratory syn- Videocast live and archived: https://video- We are all in this together, even if we are drome coronavirus 2 (SARS-CoV-2). cast.nih.gov physically apart. In early 2020, as the world was just For a full list, go to https://oir.nih.gov/sigs/ learning of a strange and alarming new covid-19-scientific-interest-group Links virus infecting people in southeast China, • May 6: “Animal Models for COVID- • NIH Civil Program: https://hr.nih.gov/ NIHers already were at work investigating 19: A Critical Component of the Response working-nih/civil the nature of what would become known as to the Pandemic,” by Emmie De Witt, • Employee Assistance Program: https:// SARS-CoV-2. Researchers at the National Ph.D., Chief, Molecular Pathogenesis Unit, www.ors.od.nih.gov/sr/dohs/HealthAndWell- Institute of Allergy and Infectious Diseases Laboratory of Virology, NIAID ness/EAP/Pages/index.aspx (NIAID), in particular, were among the • May 13: “Adaptive Clinical Trial • OITE: https://www.training.nih.gov first in the United States to assess this Design,” by Lori Dodd, Ph.D., Mathe- • Occupational Medical Service: https://www. emerging threat. NIH then combined matical Statistician, Biostatistics Research ors.od.nih.gov/Pages/home.aspx (and click on this initial assessment with years of ongo- Branch, NIAID OMS) ing research on pandemics, in general, and • May 20: “Infection Control in • Division of International Services: https:// on coronavirus, specifically, to inform other COVID-19,” by Tara Palmore, M.D., www.ors.od.nih.gov/pes/dis/Pages/default. health authorities. Hospital Epidemiologist, Clinical Center aspx The NIH constitutes an exceptional • More to be scheduled. • Office of the Ombudsman: https://ombuds- pool of scientific talent. It’s only natural, man.nih.gov then, that so many of you have turned The PIs who lead or moderate this • NIH Guidance for Staff on Coronavirus: your focus to studying SARS-CoV-2 and new group were culled from a far larger https://employees.nih.gov/pages/coronavirus COVID-19 in your respective discipline, list of volunteers and represent the scientific • Scientific Interest Groups: https://oir.nih. be it immunology, virology, epidemiol- diversity of the NIH: Mario Borgnia gov/sigs ogy, structure biology, computational sci- (NIEHS), Carson Chow (NIDDK), • Other Affinity Groups: https://www.training. ence, bioengineering, pandemic modeling, Michail Lionakis (NIAID), Vinay Pathak nih.gov/you_are_not_alone animal modeling, or another. Coordinating (NCI), Kaitlyn Sadtler (NIBIB), Pam these activities will be a major focus of the Schwartzberg (NIAID), and Irini Sereti Archived videocasts COVID-19 SIG. • WALS: http://videocast.nih.gov/PastEvents. (NIAID). The NIH Office of Intramural Research representative is Charles Dearolf asp?c=3) LISTSERV and MS Teams ([email protected]). • Clinical Center Grand Rounds: http://video- • The COVID-19 SIG has launched a cast.nih.gov/PastEvents.asp?c=27 LISTSERV email newsletter, which is For more information about the COVID-19 • Demystifying Medicine: https://videocast. open to scientists and staff at NIH and Scientific Interest Group, go to https://oir.nih. nih.gov/PastEvents?c=45 HHS. Although the LISTSERV news- gov/sigs/covid-19-scientific-interest-group. letter can only accept subscribers within
https://irp.nih.gov/catalyst 3 THE TRAINING PAGE
From the Fellows Committee The Potential Path from Ph.D. to Medical Science Liaison BY CRAIG MYRUM, NIA
Are you as good with people as you experience. But with sufficient prepara- in discussions with the hiring company.” are with a pipette? Can you cut down on tion and understanding of MSL roles and Here is some insight from McNabb’s scientific jargon to effectively communicate responsibilities, opportunities will open five years of MSL experience: “People with science with anyone? What about your up for bench scientists and clinicians alike. advanced degrees are often conditioned to leadership and critical-thinking skills? If “First, convert your CV [into] a resumé,” engage in chronic self-doubt, and I regularly you envisage a career outside of academia McNabb suggested. “This will be neces- find in my discussions with postdocs that and these qualities seem to describe you, sary for a transition to industry. Summarize self-doubt is a significant mental hurdle that consider transitioning into a role as a your qualifications by listing your experience needs to be overcome before the job search Medical Science Liaison (MSL). presenting, teaching, mentoring, and work- even begins. So let me assure you that you MSLs are not pharmaceutical sales ing on teams. These are the most important do have skills that are valuable outside of representatives, but are scientific experts skills for MSLs, and they’re exactly what academic laboratory research. Your skills are who are increasingly essential resources hiring managers want to hear.” transferable to a different career pathway. to colleagues within their own company You will also need to be thoroughly And if you assess your experience honestly and to physicians at academic medical prepared for interviews. It’s key to prepare and match it with a fitting career path, you institutions and clinics. In short, MSLs seek carefully for behavioral interviews (which are will find a position that fulfills you. In other to connect health-care companies (such as based on discovering how the interviewee words, keep your head up, stay confident, pharmaceutical companies, biotech firms, acted in job-related situations). OITE can and don’t count yourself out.” and medical-device businesses) with health- help you by providing opportunities for care professionals who treat disease. mock interviews and offering training on Related Links Now may be a good time to get into the how to use the STAR interview format (situ- • Medical Science Liaison Society: http://www. field. According to a 2018 survey conducted ation, task, actions, and results) to answer themsls.org by the Medical Science Liaison Society, 68% the inevitable behavioral interview questions. • OITE Events: https://www.training.nih.gov/ of MSL managers plan to expand their MSL Aspiring MSLs should also be aware events/upcoming teams. But how can trainees break into the of several other key resources. First, fellows field without experience? should use LinkedIn. The networking “When I decided I wanted to pursue platform is of much greater importance Frolicking Foxes the MSL career pathway, the Office for MSLs than for those in research— of Intramural Training and Education both for finding jobs and for fostering and (OITE) was an invaluable asset,” said Chris maintaining professional relationships. The McNabb, a former postdoctoral fellow at MSL Society, a nonprofit organization
the National Center for Complementary dedicated to advancing the MSL profession, JAMIE SCHETROMPF, NIDCR and Integrative Health. “I recommend all can also be a valuable resource. It offers a aspiring MSLs look into the resources they host of tools for those interested in an MSL offer.” McNabb, who is now a Senior MSL career including regular webcasts for skill in oncology at Bayer Pharmaceuticals, found development and annual salary surveys that that the NIH Career Symposium and one- are useful when negotiating job offers. Lastly, on-one meetings with career counselors were become familiar with recruiting firms and particularly valuable. Counselors can help their talent-acquisition specialists, and These fox kits were playing outside their den next to with everything from writing your resumé connect with them on LinkedIn. “They the front doors of Building 30 when Jamie Schetrompf happened to walk by and snapped a photo with his cell to negotiating an offer. are incentivized to place people just like phone. “They had run over by the benches and under the For those doing clinical research, the you in the positions you’re looking for,” trash can playing with each other,” said Schetrompf, who transition to an MSL role may be smoother said McNabb. “They know the latest job works in the National Institute of Dental and Craniofacial Research’s Veterinary Resources Core and is on campus than for bench scientists who lack clinical postings, and they will serve as your advocate every other week during the COVID-19 pandemic.
4 THE NIH CATALYST MAY-JUNE 2020 FEATURE
Rare Disease Day and the DADA2 Story It Takes Detective Work to Diagnose Rare Diseases BY CHARLESICE HAWKINS, OD
count dropping. Chambers took her to the Mayo Clinic (Rochester, Minnesota) and even the doctors there couldn’t figure out what might be wrong other than diagnosing her with immunodeficiency. That same year, Allie’s younger brother Trey (age 6) developed nodules just like his sister’s. The Mayo physicians, suspecting a hereditary link, sent samples of the siblings’ blood to Baylor College of Medicine (Houston) for then-cutting-edge whole- exome sequencing. Simultaneously, the doctors made a blog post about the case. A doctor from Finland responded and
CREDIT: NCATS CREDIT: suggested testing the children for adenosine
Vanderbilt University physician Chip Chambers (left), who has two children with the rare disease DADA2, and NIH deaminase 2 (ADA2) deficiency. At the pediatric rheumatologist Amanda Ombrello (right), who also has a child with a rare disease, shared their stories at NIH’s time, there were no scientific journal articles Rare Disease Day in February. on the disease so, in essence, the disease did not “really” exist. The Finnish doctor Many aspects of Sherlock Holmes’s collaborations among scientists, doctors, went on to describe that symptoms might famous detective skills and eccentric and the community—help to make progress include intermittent fevers, mottled skin mannerisms were modeled after one of toward quicker diagnoses of rare diseases. discoloration, immunodeficiency, bone- Sir Arthur Conan Doyle’s medical school “Rare stories,” about the detective marrow failure, and recurrent strokes that professors, Dr. Joseph Bell. Bell was known work required to find such diagnoses, may begin in childhood. for using close observation to diagnose were highlighted at the conference. One of The Chambers children had most of the diseases. He was reputed to be able to the stories began on a hot summer day in symptoms, but not strokes. Blood samples deduce a stranger’s occupation and recent 1999 in Nashville, Tennessee. Two-year- sent to Finland confirmed that the ADA2 activities based on the greeting they chose old Allie Chambers was playing outside enzymatic concentrations were virtually and minute details such as the dirt on their when small nodules suddenly appeared on undetectable, which further supported the shoes. If only Sherlock Holmes or Dr. Bell her legs. Allie’s father—Chip Chambers, a diagnosis. The children were subsequently could closely observe patients with rare physician at Vanderbilt University Medical found to have mutations in the ADA2 gene. diseases today, perhaps it would shorten the Center (Nashville)—took her to a pediatric While the Chambers family was years-long diagnostic odysseys that many dermatologist for a medical exam, beginning undergoing their diagnostic odyssey, a of them face. her nearly 15-year-long diagnostic journey. seemingly separate and unrelated set of At the Rare Disease Day conference, held The pediatric dermatologist suggested the girl odysseys were ongoing at NIH in Bethesda, at NIH on February 28, 2020, health-care had flea bites, but Chambers knew that wasn’t Maryland. In 2002, a 2-year-old girl providers, patient advocates, and patients with possible since the family did not have a dog. presented to the NIH Autoinflammatory rare diseases shared their remarkable stories. A few months later, a skin biopsy revealed Disease Clinic for evaluation of her fevers, The day was filled with talks, posters, and that Allie had very inflamed vessels in her strokes, and rash. At the time, she did panel discussions, including “Shortening the skin and unusual-looking cells surrounding not exhibit any of the features of known Diagnostic Odyssey,” which emphasized how the vessels. But no one could diagnose what autoinflammatory diseases. advances in genomics, medical informatics, she had. In 2010, she became very sick with and novel clinical approaches—as well as her liver functions going awry and her platelet CONTINUED ON PAGE 19
https://irp.nih.gov/catalyst 5 FEATURE
Revolutionizing Science Two Nobel Laureates Wow WALS Audiences BY MEGAN KALOMIRIS, NIAID, AND EMILY MEYER, NEI
The two Nobel Laureates—Frances Biochemistry there. Her research in chemistry—as it is in its original form. Arnold and James Allison—who presented involves using evolution to create Arnold’s lab uses directed evolution WALS lectures this winter were notable enzymes that drive chemical reactions. to create other enzymes that catalyze for their “firsts.” Arnold was the first The Wednesday Afternoon Lecture the production of pharmaceuticals, American woman to receive the Nobel Series was proud to host her on biofuels, and other chemicals we use Prize in Chemistry. James Allison was the February 25, 2020. regularly. The enzymes can replace toxic first to present a virtual WALS lecture When Arnold joined Caltech, she chemical compounds normally used in in this historic time of the COVID-19 began using DNA technology to engineer the catalyzation process. Her team starts pandemic. new enzymes that could be used to with an enzyme, creates several genetic produce pharmaceuticals, plastics, and blueprints of it, each with a different other chemicals. She hoped to create mutation affecting the enzyme’s site of enzymes that would be a safe, sustainable activity. These genetic blueprints are alternative to the toxic chemicals currently then put into Escherichia coli bacteria to used in the creation of everyday products. secrete the enzymes, and the researchers But after a couple of years of failed screen those to determine which mutation attempts of trying to “rationally” design works best. The process can be repeated new enzymes, Arnold realized she must to accumulate beneficial mutations that take a different approach. “You can read, optimize enzyme performance. Often write, edit DNA,” she said, “but we don’t after introducing only a few mutations, know how to compose it.” Arnold’s team evolves well-functioning In the early 1990s, she pioneered enzymes with capabilities beyond what “directed evolution” (a method that is seen in nature, including the ability to mimics the process of natural selection) catalyze reactions not known in biology. to optimize existing enzymes and create Arnold continues to create enzymes new ones. In her first attempt, she as sustainable, environmentally friendly engineered a new version of subtilisin—an replacements for chemicals currently Frances Arnold enzyme derived from the bacteria Bacillus used in industry. “Let’s use some of [the subtilis—that normally functions in the biological world’s] best design tools,” Frances Arnold’s watery environment of a cell. Subtilisin is Arnold said at the end of her talk. “Let’s used in detergents and household cleaning learn how to use evolution ourselves, so Revolution of products to remove proteinaceous deposits that maybe we can learn to survive on Evolution and stains. this planet, if not thrive.” BY MEGAN KALOMIRIS, NIAID Arnold introduced different mutations into the aprE gene that encodes for In 2018, the Nobel Prize in subtilisin and then inserted the mutated chemistry was awarded to an American genes into separate colonies of bacteria The 2019-2020 WALS season was woman for the first time—Frances to produce new enzymes. Arnold then interrupted by the COVID-19 pandemic Arnold, who’s been at the California picked the bacteria producing the best and lectures are being rescheduled. Institute of Technology (Pasadena, enzyme and started the process again WALS is expected to resume in California) since 1986 and is currently with that mutated gene. After several September 2020. Visit the WALS website the Linus Pauling professor of Chemical rounds, she wound up with a version of for updates: https://oir.nih.gov/wals. Engineering, Bioengineering, and subtilisin that was 256 times as active in dimethylformamide—a common solvent
6 THE NIH CATALYST MAY-JUNE 2020 FEATURE
least three years and many lived 10 years and longer). In 2015, Allison won a Lasker Award in recognition of his achievements. He is also exploring how another immunotherapy treatment with a PD-1 inhibitor drug, nivolumab, helps T cells fight cancer. PD-1 suppresses the tumor-killing activity of T cells and works via a different pathway than CTLA4 does. Nivolumab has shown promising results when used on many types of cancers including melanoma and lung cancer. Allison explained how the drugs perform better together than alone and
CREDIT: JACQUELINE ROBERTS, ODCREDIT: predicted that the future would bring more Nobel Laureate James Allison delivered his WALS lecture from an empty auditorium at MD Anderson Cancer Center combinations of PD-1 and CTLA-4. in Houston to a small audience in NIH’s Wilson Hall (Building One) while more than 1,000 people watched remotely. It used to be that the only way to fight cancer was to attack tumors and malignant Rosenberg, another cancer-immunotherapy James Allison’s cells directly. But Allison’s immunotherapy pioneer, and more than 1,000 people who approach—treating the immune system Revolutionary Cancer watched remotely. instead of the tumor—may one day defeat Allison’s research on T cells and Treatment even the most untreatable cancers. BY EMILY MEYER, NEI checkpoint blockades revolutionized cancer treatment and won him a Nobel Prize in To watch a videocast of James Allison’s WALS In the fight against cancer, the Physiology or Medicine in 2018. He and talk, held on March 11, 2020, go to https:// immune system may be a better drug Tasuku Honjo (NIH fellow in the 1970s; videocast.nih.gov/watch=36081. target than the cancer itself. This was the Fogarty Scholar-in-Residence in the 1990s) vision presented, on March 11, 2020, by shared the prize “for their discovery of Nobel Laureate James Allison during cancer therapy by inhibition of negative NIH’s first-ever virtual presentation for immune regulation.” NIH’s Wednesday Afternoon Lecture Allison described his work with two Series (WALS). molecules—cytotoxic T-lymphocyte The WALS lecture was held virtually protein 4 (CTLA4) and programmed cell because of the COVID-19 pandemic death protein 1 (PD-1)—that function as and public-health concerns regarding immune checkpoints. They downregulate nonessential travel and large group immune responses by blocking the T cells’ gatherings. Allison delivered his lecture ability to attack cancer cells. To override from an empty room at the University the block, he developed an anti-CTLA4 of Texas MD Anderson Cancer Center antibody, which eventually became the drug (Houston), where he is the chair of the ipilimumab. In 2011, the FDA approved the Department of Immunology. The NIH use of the drug to treat late-stage melanoma; “audience” consisted of five people in NIH’s it was the first drug to extend the survival Wilson Hall (Building One) including NIH of those with that cancer. (Survival used to
Director Francis Collins and National be about four months from diagnosis, but James Allison Cancer Institute senior investigator Steven with the drug more than 20% lived for at
https://irp.nih.gov/catalyst 7 CATALYTIC RESEARCH Intramural Research Briefs
which enhances the formation of ATP. The senior author of the study. “This [blocking] knock-out syntaphilin mice showed the most might delay the progression of the disease. robust axon regrowth in the injured area. These But we won’t know until we try it.” (NIH findings suggest that enhancing mitochondrial authors: D. Rajapakse, K. Peterson, S. Mishra, axonal transport by depleting syntaphilin J. Fan, J. Lerner, M. Campos, and G. Wistow, and increasing the energy supply within the Transl Res 219:45–62, 2020; DOI:10.1016/j. injured spinal-cord nerves could promote trsl.2020.02.007) regeneration and functional restoration after [BY DIPTADIP DATTAROY, NIDDK] spinal-cord injuries. (NIH authors: Y. Xie, N. Huang, K.A. Chamberlain, and Z.H. Sheng, NCI, NIA: HIGHER DAILY STEP COUNT LINKED Cell Metab 31:623–641, 2020; DOI:10.1016/j. WITH LOWER RISK OF DEATH cmet.2020.02.002) Z.H. SHENG LAB, NINDS Should one strive to take more steps per day? A [BY EMILY MEYER, NEI] NINDS scientists have found they can help spinal cord recent observational study, conducted by NCI, nerves regrow by enhancing mitochondrial axonal transport NIA, and CDC investigators, found that higher and increasing the energy supply to the damaged nerves. Shown: Spinal cord injury (black area at top); scar formed NEI: TOOTH-ENAMEL PROTEIN MAY BE daily step counts—but not the intensity of by glial cells (cyan) that surround neurons; undamaged THERAPEUTIC TARGET FOR BLINDING stepping—were associated with lower mortality nerves (red) to left of injury; nerves (red) that have regrown (to right of injured area). DISEASE risk from all causes. NEI researchers have discovered that the The study was conducted through NINDS: REPLENISHING NEURONAL protein amelotin, which normally deposits the CDC’s National Health and Nutrition MITOCHONDRIA LEADS TO SPINAL CORD mineralized calcium in tooth enamel, may Examination Survey, allowing for data REGROWTH play a role in the development of dry age- collection from a representative sample After spinal-cord injuries, many patients have related macular degeneration (dry AMD). Dry of U.S. adults aged 40 years and over. The difficulty recovering due to the seemingly AMD, for which there is no treatment, causes participants wore accelerometers for seven permanent damage to their axons, or nerve progressive loss of vision due to the death of days (2003–2006) so researchers could fibers. In studies conducted on mice, NINDS the retinal pigment epithelium (RPE) and the track step counts and step intensity (steps/ researchers and colleagues from the Indiana photoreceptor cells. Deposits (some are called minute). The participants were then followed University School of Medicine (Indianapolis) soft drusen) of cholesterol, lipids, proteins for mortality through December 2015 via the have discovered potential mechanisms for (including amelotin), and minerals accumulate National Death Index. axonal regrowth. They have identified impaired at the back of the eye. Amelotin is responsible This study found that, compared with mitochondria as a key target. for the deposition of a calcium-containing taking 4,000 steps, taking 12,000 steps The energy-generating mitochondria mineral compound called hydroxyapatite per day (walking about six miles) was the are critical for promoting axon growth. (HAP), a key component in tooth enamel and healthiest option and associated with 65% One of their primary functions is creating bone, in the back of the eye. lower risk of all-cause mortality. Taking 8,000 adenosine triphosphate, or ATP, our body’s The researchers discovered that if steps per day (walking about four miles) fuel source. But when the spinal cord axons are they starved cultured RPE cells for nine was associated with a 51% lower risk. The damaged, the nearby mitochondria are often days, the cells began to deposit HAP. The researchers were surprised that they didn’t damaged and lose their ability to produce nutritional stress upregulates amelotin find an association between the intensity of ATP. Compounding the problem is that in protein expression, which augments HAP stepping and all-cause mortality. adult nerves, damaged mitochondria can’t be mineralization in RPE cell culture. Inhibiting The findings confirm recommendations replaced because they are kept stationary by amelotin expression in the RPE cells blocks that to stay healthy, adults should be more the protein syntaphilin. this event. By examining human cadaver physically active and sit less during the day. The scientists observed, however, that— eyes, the researchers verified that HAP and (NIH authors: P.F. Saint-Maurice, R.P. Troiano, compared with control animals—syntaphilin- amelotin occur only in eyes with dry AMD. B.I. Graubard, E.J. Shiroma, and C.E. Matthews; knockout mice show significantly more axonal “Conceptually, you could see coming up JAMA 323:1151–1160, 2020; DOI:10.1001/ regrowth after spinal-cord injury. In further with drugs that specifically block the function jama.2020.1382) experiments, the mice were given creatine, of amelotin in eye,” said Graeme Wistow, [BY CAROLINE DUNCOMBE, NIAID]
8 THE NIH CATALYST MARCH-APRILMAY-JUNE 2020 2020 CATALYTICCATALYTIC RESEARCHRESEARCH
NIEHS: AUTOIMMUNITY MAY BE RISING IN THE that they could thwart the tumors’ response by UNITED STATES disabling key enzymes in the VEGF signaling A group of NIEHS researchers has shown pathway. that autoimmunity appears to be increasing Interestingly, the downstream cellular in the United States. They found that serum pathway of these growth factors involves concentrations of antinuclear antibodies enzymes that convert the compound PIP2 (ANAs)—a biomarker observed in most into substrates that drive the process of CREDIT: L. WANG AND C. GERFEN, NEI GERFEN, C. AND WANG L. CREDIT: autoimmune conditions—have steadily risen angiogenesis. These substrates are converted over the last 25 years, particularly in males, back into PIP2 through a PI-recycling system non-Hispanic whites, adults 50 years and that enables the angiogenesis process to older, and most alarmingly in adolescents. continue. The researchers showed they could The study included 14,211 participants, 12 stop the growth of tumors by blocking any of years and older, in the U.S. National Health the enzymes in this PI-recycling series. and Nutrition Examination Survey. Using The scientists showed that disruption of immunofluorescence, a technique that uses the PI-recycling system significantly decreased fluorescent dye to visualize antibodies, the angiogenesis in zebrafish Danio( rerio) embryos NEI, NIMH: Slice of mouse brain showing neurons of the researchers examined the frequencies of ANAs and chemically treated human endothelial superior colliculus (white) highlighted on one side. in subjects from three time periods: 1988– cells, and slowed the growth of pre-existing center in the brain for processing basic visual 1991, 1999–2004, and 2011–2012. Only 11% of tumors in mice (Mus musculus). For the first events—could be controlled via optogenetics. participants in 1988–1991 had detectable ANAs two models, the researchers either disabled Optogenetics is the technique of using a in their serum, but ANA prevalence rose to the genes for one or more of the enzymes beam of light to turn neurons on and off. 11.5% in 1991–2004 and to 15.9% in 2004–2012. or administered drugs that that blocked the Those mice were shown a Gabor patch (a Teenagers had the largest increases—from recycling enzymes. For the mouse model, they pattern used as a visual stimulus) and trained a twofold increase to a threefold increase targeted the tumors with both genetic and to lick a spout when they perceived a change over the three time periods. The scientists chemical ablation of recycling enzymes. In their in the patch’s orientation. suggested that changes in lifestyles or the paper, the authors concluded that the “findings When the researchers used optogenetics environment might be to blame. Further highlight the role that phosphoinositide to temporarily turn off neurons in the SC, studies are needed to delineate possible recycling plays in tumor angiogenesis, and they found that the inhibition had to occur causes and develop preventative measures. suggest that targeted inhibition of PI recycling within a specific 100-millisecond interval (NIH authors: C.G. Parks, C.R. Weinberg, D.C. may provide a useful anti-angiogenic modality after the visual event; if the inhibition was Zeldin, and F.W. Miller, Arthritis Rheum 2020; for the treatment of cancer.” (NIH authors: A.N. outside that 100-millisecond timeframe, the DOI:10.1002/art.41214) Stratman, O.M. Farrelly, C.M. Mikelis, M.F. Miller, mouse’s decisions were mostly unaffected. [BY SUNITA CHOPRA, NCI] Z. Wang, V.N. Pham, A.E. Davis, M.C. Burns, Understanding these mechanisms by S.A. Pezoa, D. Castranova, J.J. Yano, T.M. Kilts, which visual information is processed has J.S. Gutkind, and B.M. Weinstein, Nat Commun NICHD, NIDCR: TARGETING A SIGNALING implications for conditions that affect visual 11:article number 1204, 2020; DOI:10.1038/ PATHWAY TO PREVENT TUMOR GROWTH perception and attention, such as attention- s41467-020-14956-z) NICHD AND NIDCR scientists and colleagues deficit hyperactivity disorder. (NIH authors: [BY KANCHAN GUPTA, NINDS] at other institutions developed a way to stop L. Wang, K. McAlonan, S. Goldstein, C.R. tumors from growing new blood vessels Gerfen, and R.J. Krauzlis, J Neurosci, 2020; (angiogenesis). Cellular signaling by growth NEI, NIMH: VISUAL EVENTS HAVE 100 DOI:10.1523/JNEUROSCI.2642-19.2020) factors such as vascular endothelial growth MILLISECONDS TO HIT BRAIN TARGET [BY MEGAN KALOMIRIS, NIAID] factor (VEGF) play a vital role in tumor NIH scientists have defined a 100-millisecond angiogenesis. Anti-angiogenic therapies aimed window that determines whether the Read more briefs and longer versions of at directly blocking VEGF are overwhelmed by brain notices or ignores visual events. The these at: https://irp.nih.gov/catalyst/ the tumors’ ability to produce more of this researchers used genetically modified mice v28i3/research-briefs. growth factor. The researchers found, however, in which the superior colliculus (SC)—a major
https://irp.nih.gov/catalyst 9 FROM THE ANNALS OF NIH HISTORY
1918 Flu Memoir CONTINUED FROM PAGE 1 communicable diseases by aiding state and confined to my room that Washington local boards of health or otherwise.” experienced a very serious epidemic. Dr. Some of the medical officers of the McCoy became a part-time physician, taking Hygienic Laboratory were sent into the field. care of the Laboratory’s personnel who were Those who remained laid aside their research ill with uncomplicated influenza, in addition projects to organize emergency hospitals, to his administrative work. Dr. [James] or to become practicing physicians caring Leake took care of government workers for sick government workers. Due to the who were seriously ill with pneumonia in absence of the doctors, and to the illness of temporary hospitals. many others of the Laboratory personnel, Years later: I heard a minister say that only a few were left to carry on. during the worst days of those weeks, burial I presume that there may have been a services in Washington cemeteries had to be demand that the government agency should curtailed in order that each funeral cortege attempt to to find the cause of the epidemic. could move along promptly to make room However that may be, about the middle of for the next. the month [Hygienic Laboratory Director] When I returned to the Laboratory, Dr. [George] McCoy asked me to drop my I resumed my studies on meningococci, CREDIT: NATIONAL LIBRARY OF MEDICINE current problem and turn my attention to for the war was over, the peak of the the subject of greatest concern. epidemic in Washington had passed, At that time bacteriologists were and conditions were more favorable for considering whether the “influenza bacillus” clear-headed thinking. It was recognized of Pfeiffer Haemophilus( influenzae), which that the search for the etiologic agent of was found quite constantly in cases of influenza was not a problem for a lone influenza, was or was not the etiologic investigator. It became a major project of agent of this disease. In later years it was study in more than one institution (but not considered to be a secondary invader. at the Hygienic Laboratory), and about My first thought was that I would fifteen years later a team of investigators Alice Evans, one of the first women scientists to work at NIH (1918–1945), did research that led to the recognition of examine the sputum of patients and tissues in a London laboratory discovered that brucellosis as a public-health problem and the acceptance taken at autopsy to find the dominating the causal agent is a virus. of the need to pasteurize milk. bacterial species. That study would require a special culture medium. As our media About Alice Evans (1881–1975) maker was ill, I went to the media-room to make it myself. Alice Evans was one of the first to believe a woman without a degree. Things were not going well, and I knew women scientists to work at NIH. Evans began her federal civil-service that I was not skillfully undertaking this Her research led to the recognition of career in 1910 with the U.S. Department job of making media to which I had long brucellosis as a public-health problem of Agriculture (USDA) in Wisconsin. been unaccustomed. Gradually I realized and the acceptance of the need to In 1913 she moved east to Washington, that there was something the matter with pasteurize milk. She received her B.S. D.C., to work in the newly completed me, more than the feeling of helplessness on in bacteriology from Cornell University laboratories of the USDA Dairy Division. being assigned unexpectedly to an enormous (Ithaca, New York) in 1909 and her In 1918, she inquired of the Hygienic task. Finally I guessed it—I was coming M.S. from the University of Wisconsin Laboratory whether her services might down with the flu. I put away utensils and (Madison, Wisconsin) in 1910. She never be of use in connection with the wartime ingredients and went home. A little more did earn her Ph.D., which caused a delay effort; she was hired as a bacteriologist. than a month later I returned to work. in the acceptance of her research findings She joined a team working to improve the It was during those weeks when I was on brucellosis and milk. Male scientists serum treatment for epidemic meningitis. and milk manufacturers found it hard Evans retired from NIH in 1945.
10 THE NIH CATALYST MAY-JUNE 2020 FEATURE
NIH 2020 Timeline Highlighting Selected COVID-19 Activities
January 23: NIH officials discuss novel March 18: A new COVID-19 Scientific Interest decontamination methods for re-use of N95 coronavirus that recently emerged in China Group is established. respirators. (non-peer-reviewed preprint server January 29: President Donald Trump March 20: NIH shifts non-mission-critical lab medRxiv, April 24, 2020; DOI:10.1101/2020.04 announces the formation of the Coronavirus operations to minimal maintenance phase. .11.20062018) Task Force, which includes HHS Secretary Alex March 20: NIH holds its first virtual town hall April 15: NIDDK investigators report the Azar and NIAID Director Anthony Fauci. meeting on the coronavirus response. More results of a laser-light-scattering experiment February 13: NIAID researchers publish paper than 24,000 have watched the broadcast. that provided visual evidence of how speech- showing that the experimental antiviral March 23: NIH announces launch of COVID-19 generated droplets moved through the air remdesivir prevents MERS coronavirus disease virtual–training site for frontline responders. and that putting a damp cloth over the mouth in monkeys. (Proc Natl Acad Sci USA, 2019; March 23: Maryland prohibits large gatherings decreased the number of droplets. (New Engl J DOI:10.1073/pnas.1922083117) and events and closes senior centers and all Med, 2020; DOI: 10.1056/NEJMc2007800) Feb 25: The NIAID-sponsored the first clinical non-essential businesses. April 17: NIH announces a public-private trial of remdesivir to treat COVID-19 begins at March 24: Clinical Center (CC) enrolls first two partnership (called ACTIV)—including 16 the University of Nebraska Medical Center. participants in NIAID remdesivir trial. biopharmaceutical companies, HHS, CDC, FDA, March 3: President Trump visits NIAID’s Vaccine March 25: The National Library of Medicine and the European Medicines Agency—to speed Research Center to discuss coronavirus. expands access to coronavirus literature COVID-19 vaccine and treatment options. March 6: NIH launches its Coronavirus through PubMed Central. April 17: NIDCR begins enrolling participants Response Team, which begins meeting March 26: Screening of all staff members for a study to determine whether SARS-CoV-2 daily. Co-chairs are NIH Principal Deputy entering Building 10 begins. is in the saliva of asymptomatic individuals. Director Lawrence Tabak and NIH Director for March 27: An Atlanta site is added to the clinical April 17: Early treatment with the experimental Management Alfred Johnson. trial of the NIAID's vaccine for COVID-19. antiviral drug remdesivir significantly reduces March 10: CC starts deferring elective patients. March 27: In the CC, surgical masks are required clinical disease and damage to the lungs March 12: CC starts screening patients and for everyone doing direct patient care. of rhesus macaques infected with SARS- visitors coming into Building 10. March 30-April 1: Stay-at-home orders for CoV-2, according to NIAID scientists. (non- March 15: NIH reports first known employee Maryland, Virginia, and Washington, D.C., take peer-reviewed preprint server bioRxiv,2020; with COVID-19 infection. effect. DOI:10.1101/2020.04.15.043166) March 16: Most NIH employees and trainees April 2: NIDA Director Nora Volkow outlines April 17: The NIAID-supported clinical trial begin teleworking; telework is now extended the potential risks to people who smoke and of an experimental COVID-19 vaccine begins through May 31. use drugs during the COVID-19 pandemic. (Ann enrolling older adults. NIH is now a site. March 16: Closure of all schools in Maryland, Intern Med, 2020; DOI:10.7326/M20-1212) April 21: Expert U.S. panel—including co-chairs Virginia, and Washington, D.C., begins. April 2: The NIH CC provides surgical masks to H. Clifford Lane (NIAID) and Henry Masur March 16: An NIH-funded clinical trial of an everyone who enters the building. (CC)—develops NIH treatment guidelines. NIAID-developed investigational vaccine for April 9: NHLBI begins a clinical trial in Nashville April 22: DDIR Michael Gottesman announces COVID-19 begins in Seattle. to evaluate the safety and effectiveness of the Intramural Targeted Anti-COVID-19 (ITAC) March 17: NIH establishes large-scale, hydroxychloroquine to treat COVID-19. funding program made possible by NIAID. centralized COVID-19 screening (and testing, if April 10: The NIH Office of Data Science April 23: A new strategic plan from NIAID needed) for employees. Strategy has compiled COVID-19-related provides details for accelerating research to March 17: NIAID’s Rocky Mountain Laboratories resources in one website location. diagnose, prevent, and treat COVID-19. scientists and others report that the virus that April 10: NIAID begins a serology study to April 24: Second NIH virtual town hall meeting. causes COVID-19 is stable for several hours determine how many adults not diagnosed with April 29: NIH announces a $1.5 billion initiative to days in aerosols and on surfaces. (N Engl COVID-19 have antibodies to the virus. (called RADx) aimed at speeding innovation, J Med 382:1564-1567, 2020; DOI:10.1056/ April 13: Montgomery County, Maryland, development and commercialization of COVID- NEJMc2004973) requires that all shoppers wear face coverings 19 testing technologies. March 18: Many NIH campus services begin in grocery stores, pharmacies, and elsewhere. April 29: NIAID clinical trial shows that closing. The NIH childcare center remains open. April 15: A study by investigators at NIAID’s remdesivir accelerates recovery from advanced Rocky Mountain Laboratories validates COVID-19.
https://irp.nih.gov/catalyst 11 FEATURE
You Are What You Eat Profile: Emily Chew, M.D. BY EIMEAR HOLTON, NIAID
Emily Chew understands the power of nutrition, and she has the data to back herself up. Eating fish as “brain food” before taking an exam and consuming goji berries to achieve better eyesight were some of the many wisdoms she learned when growing up in a Chinese immigrant family in British Columbia (Canada). “All my life I’ve been aware [that] my whole family are foodies,” said Chew, who is a senior investigator at the National Eye Institute (NEI) and director of NEI’s
Division of Epidemiology and Clinical CREDIT: NEI Applications. Her family’s wisdom certainly proved useful. Chew’s 30-year career at the
NIH has led to instrumental clinical studies Emily Chew’s work has furthered the understanding of the influence of nutrition and genetics on blindness especially in to further our understanding of the influence slowing the progression of retinal vascular diseases such as age-related macular degeneration. of nutrition and genetics on blindness, especially in slowing the progression of “incredible in the way he looked at life and about their project and contribute in the retinal vascular diseases such as age-related how he approached patients,” said Chew. best way possible.” Wong has continued macular degeneration (AMD). “And he is the humblest person you would to collaborate with his mentor for the past ever meet.” 14 years. Influential Mentors Chew has mentors even now. She talks Chew has also mentored medical Chew’s pursuit of clinical research to leaders throughout the NIH “who have students in NIH’s Medical Research was inspired by influential mentors been very kind, considerate, and generous Scholars Program as well as people in two throughout her medical training. While with their time,” she said. “I’ve been very former programs—the NIH–Howard at the University of Toronto, where she lucky; I think at every stage of your life one Hughes Medical Institute Research Scholars received her M.D., her mentor was Brenda needs mentoring.” Program and NIH’s Clinical Research Gallie, an ophthalmologist whose research Chew has been mentoring clinician– Training Program. focused on retinoblastoma (an eye tumor scientists herself for the past 30 years. As the She strives to instill in her mentees the in children). “She was a wonderful role director of the Medical Retina Fellowship importance of research and to nurture their model,” Chew said. “She impressed upon program (2002–2017), she mentored some curiosity, just as her mentors have done for me how you could do wonderful things three dozen trainees who have gone on to her. She is delighted to see her mentees go clinically, one patient at a time. But to work in eye-research programs across the on to do great things, pursue their passions, do research you really are affecting and United States and elsewhere. and value the importance of research. impacting many more people.” “Right off the bat, [Chew’s] mentee She hopes to inspire future leaders in As a fellow at Johns Hopkins’ Wilmer is a new collaborator,” said Wai Wong, research to work with integrity above all. In Eye Institute (Baltimore), Chew began who completed a medical retina fellowship doing so, she’ll have passed on a great deal her work on macular degeneration. One of in 2007 and is now a senior investigator to them. “You can be brilliant, work hard, her ment