NATIONAL INSTITUTES OF HEALTH • OFFICE OF THE DIRECTOR | VOLUME 29 ISSUE 3 • MAY-JUNE 2021

Phage Therapy for An Insider’s Guide to the Galaxy Fighting Antibiotic- The Challenges of Life in Outer Space resistant Infections BY MEGAN KALOMIRIS, NIAID BY SUBHASH VERMA, NCI

Antibiotic resistance (AR) looms as one of the biggest public health crises of our time. AR occurs when microbes such as bacteria develop the ability to evade the drugs designed to kill them. The Centers for Disease Control and Prevention estimate that over 2.8 million people get an AR infection in the United States each year, resulting in more than 35,000 deaths. AR is rising to dangerous levels worldwide while the pipeline of new antibiotics is running dry, threatening our ability to treat common infectious diseases. But the use of bacteriophages (phages) to treat AR infections caused by bacteria offers a glimmer of hope. Phages are naturally-occurring viruses that invade bacterial cells and replicate. NASA/JPL-CALTECH CREDIT: The viral particles eventually burst This illustration depicts NASA’s Perseverance rover operating on the surface of Mars. Perseverance, which landed at the Red Planet’s Jezero Crater on February 18, 2021, will search for signs of life and test technologies that may help determine out, killing the host cell in the process. whether humans could one day inhabit the planet. Phages have coevolved with bacteria and function to keep microbe populations in Seeking signs of ancient life, NASA’s Perseverance rover (nicknamed check: Potency, self-amplification, and “Percy”) landed on Mars on February 18th, 2021. Percy joins Curiosity, Spirit, specificity make phages an attractive Opportunity, and Sojourner as America’s fifth rover to explore Mars. When might alternative to antibiotics. And phages are humans be able to visit the red planet? The answer is complicated, as Mark Shelhamer everywhere; one can assuredly find them CONTINUED ON PAGE 12 in a lake, sewage water, or farm. CONTENTS A promising treatment resurfaces FEATURES • |1| Phage Therapy |1| An Insider’s Guide to the Galaxy |10| COVID-19 Timeline Phage treatment, known as phage therapy, (March–April) |14| Searching For Answers: Update on Undiagnosed Diseases Program has a colorful history going back a century. |16| Profile: Sean Agbor-Enoh, M.D., Ph.D. After the dawn of small-molecule antibiotics DEPARTMENTS • |2| DDIR: Celebrating Asian Americans and Pacific Islanders |3| News You however, interest in the therapy quickly Can Use: Down the Drain |4| Training: Broadening Your Audience |5| SIG Beat: Three New SIGs died down, at least in Western medicine. |8, 15| Research Briefs |13 |NIH History: Walter Thomas Lingenfelter |18| Colleagues: Tenured CONTINUED ON PAGE 6 |23| Abbreviations |24| Photographic Moment: Cherry Blossoms FROM THE DEPUTY DIRECTOR FOR INTRAMURAL RESEARCH

Celebrating Asian Americans and Pacific Islanders at NIH BY MICHAEL GOTTESMAN, DDIR, AND ROLAND OWENS, DIRECTOR OF RESEARCH WORKFORCE DEVELOPMENT, OIR

In May, we celebrate Asian 1:00 p.m. This year’s lecturer is Peter Kwong. the recent changes in our practices for the American and Pacific Islander (AAPI) This lecture series honors the life and legacy selection of lab and branch chiefs. Now that Heritage Month. This is a good time of the late Kuan-Teh Jeang, a former senior these searches are more uniformly open, we to reflect on how researchers from these investigator in NIAID. encourage all qualified scientists to apply groups have enriched the NIH Intramural This is also a good time to reflect upon for these key leadership positions. It is also Research Program (IRP). One does the challenges facing Asian American worth noting that we anticipate that there not need to look any further than our and Pacific Islander scientists. One of will be no fewer than seven scientific director recent COVID-19 seminar series to the challenges has been recognizing their positions available over the next year. Again, see outstanding research presented by many different countries of origin and we encourage all qualified researchers to Helen Su (National Institute of Allergy how different their histories are within the apply for these positions, which will be and Infectious Diseases, NIAID), Peter United States and at NIH. In particular, advertised at the IRP careers website Kwong (Vaccine Research Center), the number of Pacific Islander researchers (https://irp.nih.gov/careers/faculty-level- and Yogen Kanthi scientific-careers). (National Heart, Lung, Even though scientists of Asian descent We have all been horrified and Blood Institute). have represented over 15% of the IRP’s recently by many instances NIH Distinguished in this country of bias and Investigator T. Jake senior investigators for several years, they violence directed toward Liang, who is chief represent only 7% of our lab and branch Americans of Asian descent. of the Liver Diseases As we celebrate the many, Branch and deputy chiefs and currently hold no scientific many contributions of our director of Translational director positions. Asian American and Pacific Research at the Islander colleagues, let us also National Institute of be sure that NIH remains a at NIH has always been vanishingly Diabetes and Digestive and Kidney civil and inclusive research environment small, with only some modest successes Diseases (NIDDK), has agreed to take where no one need feel insecure or in recruitment through programs such on the new role of executive ssponsor and unappreciated. The incredible tapestry of as the NIH Undergraduate Scholarship champion for the AAPI Engagement our cultural, ethnic, and racial heritage is a Program (https://www.training.nih.gov/ Committee. There are also our National strength that will sustain the creative force programs/ugsp). Even though scientists Academy of Sciences members, Wei that propels the IRP. of Asian descent have represented over Yang (NIDDK), Shiv Grewal (National 15% of the IRP’s senior investigators for Cancer Institute, NCI), Sankar several years, they represent only 7% of our Adhya (NCI), and Kiyoshi Mizuuchi lab and branch chiefs and currently hold (NIDDK). We are all fortunate to have Links to information contained in no scientific director positions. These data such incredible researchers in our midst. this essay can be found in the online suggest that we are not making effective use As part of IRP’s celebration, we will version at: https://irp.nih.gov/catalyst/ of the complete talent pool when searching continue to co-sponsor, with the NIH v29i3/from-the-deputy-director-for- for research leaders within the IRP. Office of Equity, Diversity, and Inclusion, intramural-research. Fear that we might be missing the annual Kuan-Teh Jeang lecture, which opportunities to advance individuals with takes place this year on May 20, 2021, at leadership skills was the main driver of

2 THE NIH CATALYST MAY–JUNE 2021 NEWS YOU CAN USE

Down the Drain Tips for Keeping Hazardous Waste Out of the Sanitary Sewers BY CRAIG UPSON, OD

“There’s not some sort of magic process that can do not dispose of via the drain. Instead, remove everything we put down the drain.” call DEP at 301-496-7990 for further —David Sedlak, Director of the Institute for guidance. Environmental Science and Engineering at • Chemicals that are not listed University of California, Berkeley (Berkeley, on the approved disposal list within California) the Drain Discharge Guide may be considered for drain disposal, but you The valuable research and first have to complete an application support activities performed at NIH requesting approval (VPN and NIH produce an array of waste products. credentials required) at https://spapps. Whether they are hazardous or od.nih.gov/sites/DEPAuthorizations/ nonhazardous, all must be managed SitePages/Home.aspx. Please note that appropriately. Submitting materials when pursuing this option, disposal via through waste-management services the sanitary sewer can occur only after ensures proper disposal and prevents DEP has reviewed and approved the hazardous chemicals from being application. supply which defy treatment standards. discharged into the sanitary sewer Substances such as asbestos, PFAs (per- (system of pipes that carries sewage and polyfluoroalkyl substances), and from labs, bathrooms, sinks, kitchens, You can find the Drain Discharge Guide at pharmaceuticals—a chief concern as etc., to wastewater treatment plants). https://nems.nih.gov/Documents/NIH_ it relates to NIH operations—all pose The NIH waste-management policy Drain_Discharge_Guide.pdf. Any questions significant challenges to our waste- requires that all waste be reduced to regarding the guide should be directed management systems. the greatest extent feasible to limit to the DEP by calling 301-496-7990 or In cooperation with NIH scientific any potential negative environmental emailing [email protected]. directors and the National Institute of impacts. It’s the responsibility of For links to more resources, read the online Environmental Health Sciences, the everyone at NIH to know what can and article at https://irp.nih.gov/catalyst/v29i3/ Division of Environmental Protection cannot go down the drain. news-you-can-use. (DEP) in the NIH Office of Research Wastewater treatment technologies Facilities—has developed a Drain have advanced over the years. As a Craig Upson is a Chemical Waste Technical Discharge Guide to inform staff which result, we have become overly confident Specialist in the Waste and Resource Recovery chemicals can be disposed through the in our publicly owned treatment works Branch, Division of Environmental sanitary sewer. capabilities to clean the waste we release Protection. • Only chemicals approved for drain into the sanitary sewers. Unfortunately, disposal by the DEP may be poured down there are still problems: Newly introduced the drain. chemicals may interfere with the • Surplus solid chemicals must be treatment process or pass through the disposed of through the NIH chemical- system entirely untreated. In the 1980s, waste services and not discharged down for example, some states enacted bans on the sanitary sewer. phosphates in laundry detergents because • If you are unsure whether a chemical they promoted harmful growth of algae can be disposed of via the drain, or if in waterways. you do not see the chemical on the list We continue to discover new of approved chemicals for drain disposal, chemicals in our environment and water

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

Special to the Training Page Broadening Your Audience Beyond Your Specialty Area BY JENNIFER KAGAN

Science communication has never Tip 1: Tell your audience what excites My students have told me that been more important than during you about what you do. speaking to members of the public can be the past year. Suddenly, everyone is Do you like the excitement of discovering both challenging and rewarding. It’s “an interested in a category of viruses that something before anyone else? Use an exciting challenge because…you can’t use scientists have been quietly studying analogy to explain how much we have yet all the [scientific] jargon…when you talk for decades. We all want to know when to learn about how our bodies work. You can to a general audience,” said postdoctoral life will return to normal, and we are compare what you do to being an explorer. fellow Omar Jose (National Institute searching for answers. Unfortunately, Make identifying a new protein sound as of Diabetes and Digestive and Kidney misinformation spreads faster than exciting as discovering a new planet. Diseases), who gave a short talk recently factual information: People pay attention about vaccines at a community learning to simple explanations and sometimes Tip 2: Think about your audience’s event called Celebrating Scientists. ignore what they do not comprehend. If interests and find a connection. “Whenever I give a presentation, I we want people to trust the science, we How does your specialty area connect to try to make the message as simple as have to help them to understand it. something that the average person can possible without leaving out any critical I am a nonscientist who has taught understand? When your audience includes information. It takes time to develop advanced English classes to scientists people in the general public, you may need this ability, but it pays off because it’s an through the Foundation for Advanced to explain words that are part of your vocab- excellent way to engage the audience.” Education in the Sciences since 2017. ulary as a scientist, but are new to them. For Remember, if we want people to Many of my students are quite proficient example, describing CRISPR-Cas9 gene trust the science, we need to help them in English, having studied the language in editing as genetic scissors can provide a understand it. So the next time someone depth, but they want to make better use helpful visual. If you are a basic scientist, asks what you do or wants to know about of their language skills to become more give an example of how your work is impor- your day, think of it as a communications effective communicators. I challenge my tant in providing vital information that leads challenge that you’re ready to take students to explain the important aspects to treatments and cures for diseases. on. And if you are asked to speak at of their work more clearly. your child’s school for career day, say Regardless of your native language, it Tip 3: Leave your audience wanting to “Yes!” Think of it as a communications is much easier to speak to people inside hear more. challenge, and a challenge that you’re your specialty area than to those outside Give bite-sized pieces of information in the ready to take on. your area of expertise. After all, the people simplest language possible, then pause to in your field share a common language, let your audience digest it. When your lis- Jennifer Kagan, a faculty development full of specialized terms unique to you teners get a taste of what you know and specialist with NIH’s Foundation for and your colleagues. But the more you start asking questions, you’ve succeeded in Advanced Education in the Sciences (FAES) practice speaking to people outside your communicating about science. [https://faes.org], teaches courses in English specialty, the more comfortable you will communication skills and supports faculty feel. You’ll be rewarded with interesting Tip 4: Tell a Story. in delivering high-quality, graduate-level conversations while doing your part to People of all ages love stories. One of my courses to the NIH community. Before joining educate the public about science. students likes to tell her seven-year-old son FAES in April 2021, she was English Now!’s The first step in getting your audience stories in which the main characters are Director of Program Development and held to understand what you are saying is to antibody superheroes. Wouldn’t you prefer a joint appointment with FAES, teaching get them to listen. Here are some tips that to learn about the immune system through for English Now! Outside of work, she enjoys can help when you want to engage in a her stories instead of a boring PowerPoint biking, playing Scrabble, and spending time conversation with someone who knows presentation? with her family. nothing about what you do:

4 THE NIH CATALYST MAY–JUNE 2021 THE SIG BEAT NEWS FROM AND ABOUT THE SCIENTIFIC INTEREST GROUPS

New SIG: Asian factors that drive the development of American Pacific tumors, one quickly appreciates that any given cancer is essentially a patient-specific Islander Health disease. From this perspective, precision L. ALEXANDER/THINKSTOCK.COM L. ALEXANDER/THINKSTOCK.COM The Asian American Pacific Islander in the treatment of cancer is essential in Health Scientific Interest Group (AAPI- providing the best care for patients. HSIG) is open to all in the intramural At the NCI-Center for Cancer Research’s and extramural NIH community who are (CCR’s) online PI retreat, held in March interested in research related to the health 2021, clinicians, pathologists, principal of AAPIs. The SIG provides a forum investigators, staff scientists, and staff to foster scientific communication, share clinicians expressed an interest in creating and disseminate information, facilitate a Precision Oncology Interest Group (POIG). collaborations, provide education, assess Short-term goals. 1) Discuss, plan, research needs, and make recommendations implement, and execute the current CCR to NIH leadership that aims to stimulate initiative to perform standardized genomic New SIG: Cancer research and improve the health and well- analyses (RNA sequencing, exome Metabolism being of the AAPI population. Regular sequencing, methylation analysis) on a large The Cancer Metabolism Interest activities include monthly (or quarterly) cohort of NCI patients; 2) Use these data Group aims to provide a forum for meetings as well as research and education to drive collaborative, predictive, prognostic individuals from NIH and the extramural seminars (virtual or in-person). Other biomarker discovery, and precision-therapy community to discuss basic, translational, activities may include holding conferences strategies for improving patient outcomes. and clinical research related to metabolism and lectures in collaboration with other Long-term goals. 1) Discuss and and the intersection of metabolism NIH groups and other Federal and non- implement best sample-acquisition and with immunology. The wide scope of Federal entities; conducting joint activities management practices; 2) Discuss and seminar topics will reflect the increasing with the Federal Asian Pacific American implement the best technologies and recognition that the study of subcellular, Council; and encouraging extramural informatics to help discover candidates for cellular, and whole-body metabolism program staff to develop grant-funding targeted therapies; 3) Rationally design is relevant for understanding metabolic opportunities. The SIG co-chairs are Dan clinical trials in oncology with a focus on heterogeneity, drug resistance, diets Xi (NCI) and Phuong-Tu Le (NIMHD). precise therapies that have the potential to in cancer, cancer biology, and tumor Co-advisors include Kelvin Choi maximize benefit and minimize side effects. progression. The group will meet the (NIMHD) and Xinzhi Zhang (NCATS). The POIG aims to foster effective first Monday of each month (virtually For information, go to https://oir.nih. communication across the basic and for now). Each meeting will feature gov/sigs/AAPI-HSIG or contact Dan Xi clinical research oncology communities one 60-minute presentation from an ([email protected]). and to harness NIH’s translational powers intramural or extramural senior scientist to advance cancer precision therapies. This or two 30-minute presentations from POIG effort, initially proposed byBrigitte trainees. Senior advisers are Mark Gilbert Widemann (NCI), will be co-chaired by New SIG: Precision (NCI-CCR) and Dan McVicar (NCI- NCI scientists Padma (Sheila) Rajagopal, CCR). The SIG chair is Mioara Larion Oncology Antonios Papanicolau-Sengos, and Art (NCI-CCR). For more information, go to Cancer is a constellation of diseases Shaffer; advisors are Eytan Ruppin and https://oir.nih.gov/sigs/cancer-metabolism- typified by the uncontrolled accumulation Kenneth Aldape. All are welcome to interest-group or contact Mioara Larion of cells. Given the diversity of the cell types participate and contribute suggestions for ([email protected]). that can be transformed, cancer can affect discussion topics and speakers (including nearly every tissue and organ. Taking into yourself, of course). For more information and For a full list of NIH scientific interest groups, account the variety of genetic variations, to join the LISTSERV, go to https://oir.nih. go to https://oir.nih.gov/sigs. epigenetic influences, and environmental gov/sigs/precision-oncology-interest-group.

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

Phage Therapy CONTINUED FROM PAGE 1

The exciting news is that phage therapy Series (WALS) on March 10 and March AR. The idea was simple: If the bacteria is making a comeback; recent case studies 17 respectively. evolve phage resistance by modifying have been successful in using phages as an these elements, it will compromise their experimental therapy. Evolutionary trade-offs antibiotic resistance, making the bacteria The therapy still has a long way to go Turner is the Rachel Carson Professor of susceptible to antibiotics once again. A as it is not yet generally approved by the Ecology and Evolutionary Biology at Yale synergistic treatment using phages together FDA. And, as with antibiotics, bacteria also and a prominent expert on evolutionary with antibiotics would leave little chance for develop phage resistance. The evolutionary trade-offs (he earned his Ph.D. with the antibiotic-resistant bacteria to escape. arms race between phages and bacteria has Richard Lenski, famous for his ongoing Bacteria often develop AR by expelling been going on for billions of years—which 33-year-old long-term evolution experiment drugs through proteins known as efflux is critical to understand for phage therapy on bacteria). A trade-off occurs when natural pumps. Turner showed how a phage that to become a success. Two experts, Paul selection improves one trait at the expense binds to an efflux pump of Escherichia coli Turner from Yale School of Medicine (New of another. Turner shared his findings that (E. coli) results in the selection of phage- Haven, Connecticut) and Michael Laub demonstrated how evolutionary trade-offs resistant bacteria that are now sensitive to from MIT (Cambridge, Massachusetts), between AR and phage resistance could be tetracycline. A similar approach could target shared their research on the evolutionary used in phage therapy. virulence factors. For example, his team interaction between phages and bacteria and His research team isolated phages that found a phage that invades Pseudomonas its significance to phage therapy at the NIH enter a bacterial host by selectively targeting aeruginosa by attaching to pili, hair-like Director’s Wednesday Afternoon Lecture the elements used by the bacteria to develop appendages on the surface of bacteria to CREDIT: MANOJ RAJAURE, NCI RAJAURE, MANOJ CREDIT:

Transmission electron micrograph of a bacteriophage isolated from sewage. The phage kills a pathogenic strain of E. coli isolated from a patient with a urinary tract infection.

6 THE NIH CATALYST MAY–JUNE 2021 FEATURE

help in movement and surface adherence From proteins to phages in phage therapy. Turner also believes during infection. When the bacterium Laub is a professor of biology at that his work may help answer some bigger developed phage-resistance by losing the Massachusetts Institute of Technology questions, such as how do we predict the pili, it became avirulent (more vulnerable and a Howard Hughes Medical Institute emergence of viruses in new hosts? The to the immune system) due to its inability Investigator. He studies the coevolution investigation into evolutionary trade-offs to form biofilms and to move around. of proteins and the selective pressures between phages and bacteria might just “But there is a cautionary tale, and you that drive the evolution of bacterial reveal some clues. should know what you are doing before signaling pathways (mechanisms that using phages for therapy,” Turner said. allow bacteria to process information and Subhash Verma is research fellow in NCI’s Sometimes, instead of causing a trade-off, respond to environmental changes). But Laboratory of Molecular Biology. In his spare mutations cause a trade-up; they confer “the coevolution of proteins is dear to my time, he enjoys exploring nature, playing resistance to both antibiotics and phages. heart”, he said. cricket and volleyball, and biking. The last part of Turner’s talk focused Laub’s ongoing work on the coevolution on emergency phage therapy. His team was of toxin-antitoxin (TA) protein pairs granted FDA approval to treat a patient (referred to as TA systems in bacteria) led who developed a chronic AR infection after to his foray into the world of phages. A undergoing an aortic arch replacement. They TA system consists of a toxin gene and an chose a phage that used an efflux pump associated antitoxin. The toxin is always a for entering the bacteria and predicted that protein, and the antitoxin can be either a the phage would kill the existing microbe protein or a noncoding RNA. These systems population while exerting selection pressure are widespread in the bacterial kingdom, but on the bacteria to develop phage resistance, why bacteria carry them remains a mystery. compromising their ability to maintain AR. Laub's team discovered that cloning the PAUL TURNER Consistent with the evolutionary trade-off TA systems found in several E. coli strains To view a videocast of Turner’s WALS lecture theory, a single application of the phage into E. coli K12 (a widely used laboratory “Phage Therapy to Combat Infections by and a previously ineffective antibiotic strain of the bacterium) resulted in phage Antibiotic-Resistant Bacteria,” delivered on (ceftazidime) resolved the infection with resistance. March 10, 2021, go to: https://videocast.nih. no sign of recurrence. Interestingly, the bacteria did not gov/watch=41443. In another case, a 22 year-old patient develop broad phage resistance, suggesting with cystic fibrosis undergoing pulmonary that TA systems seem to provide tailored failure had a high concentration of AR protection only against specific phages. For bacteria in her sputum. After a phage example, one of the TA systems prevents therapy treatment given via nebulizer, the production of new viral particles by her lung function improved significantly. destroying the phage RNA. These findings Interestingly, the treatment resulted in a establish TA systems in bacteria as another population of bacteria that became sensitive arm of immunity against phages in the to almost all antibiotics, opening the door ongoing evolutionary arms race. to previously unavailable treatment options. “Phages fight back,” Laub said. His Turner is hopeful that phage therapy team identified a phage variant that evolved will be used in clinics soon. To date, Yale a counter-defense against one of the TA MICHAEL LAUB New Haven Hospital has successfully systems. This phage amplified a region of To view a videocast of Laub’s WALS lecture,” treated over 13 patients with AR infections its DNA that encoded a protein capable of Innate Immunity for Bacteria Against Phage,” using the emergency therapy. And things neutralizing the toxin, allowing the phage delivered on March 17, go to https://video- are moving in the right direction; The to propagate. cast.nih.gov/watch=41451 (HHS only). hospital was recently granted FDA approval Both Laub and Turner are exploring to begin phage-therapy clinical trials. concepts with far-reaching implications

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

NINDS, NCI, NIAMS, NICHD, NEI: DNA The NIAD team had previously established DAMAGE “HOT SPOTS” DISCOVERED WITHIN a human cerebral organoid system—a small NEURONS cluster of human brain cells grown in a lab from Researchers at NIH and the University of Sussex skin cells. The cerebral organoids have been (Falmer, England) have identified “hotspots,” shown to accurately predict neurotoxicity— in neuron genomes that appear to accumulate and therapeutic benefits—of drug treatments DNA damage known as single-strand breaks in humans. (SSBs)—a finding that has the potential to The researchers infected the cerebral reshape the way we think about DNA damage organoids with pathogenic prions and then

CREDIT: NINDS NINDS CREDIT: and its role in neurobiology. tested pentosan polysulfate (an established NINDS: “Hotspots” in neuron genomes that appear to accu- The scientists found that the most antiprion compound), which successfully mulate DNA damage. Neurons (labeled in purple) show prominent concentrations of SSBs localized to delayed prion propagation when applied signs of an active DNA repair process (labeled in yellow). The cells’ DNA itself is labeled in cyan (in this image, over- distinct regions of DNA called enhancers, which both prophylactically and after an established lap between cyan and yellow appears green). control nearby gene activity. One way a cell infection. The findings demonstrate the utility can influence gene expression is by applying of cerebral organoids as a model for screening NCI: ENGINEERED IMMUNE CELLS MAY a chemical tag known as a methyl group to therapeutic drug candidates to treat human PREVENT CANCER SPREAD specific sites on its DNA; SSBs accumulated prion diseases.(NIH authors: B.R. Groveman, Scientists at NCI have developed a form of when the methyl group had been removed. N.C. Ferreira, S.T. Foliaki, R.O. Walters, C.W. immunotherapy that prevents and slows The researchers proposed that the absent Winkler, B. Race, A.G. Hughson, and C.L. Haigh, cancer metastasis in mice. They studied mice methyl group resulted in the formation of Sci Rep 11:Article number 5165, 2021) implanted with rhabdomyosarcoma, a type SSBs. And, at least in neurons, the failure to [BY NATALIE HAGEN, NCATS] of cancer that develops in the muscles and properly repair DNA damage, not the damage

spontaneously metastasizes to the lungs. The itself, could dysregulate gene expression, NICHD: CAFFEINE DURING PREGNANCY MAY team first examined immune cell changes in the thereby contributing to the development of LEAD TO SMALLER BIRTH SIZE lungs before metastasis but after muscle-tumor neurodegenerative diseases. (NIH authors: W. NICHD researchers found that women who development. They found that several immune Wu, S.E. Hill, W.J. Nathan, J. Paiano, E. Callen, consumed as little as the equivalent of a half cell types—in particular myeloid cells—were D. Wang, K. Shinoda, N. van Wietmarschen, cup of coffee a day (50 milligrams) had slightly attracted to the premetastatic site. However, J.M. Colón-Mercado, D. Zong, R. De Pace, smaller babies than women who did not drink instead of sending signals to recruit cancer- H. Shih, S. Coon, M. Parsadanian, R. Pavani, caffeinated beverages. fighting immune cells, the myeloid cells were S. Park, S.K. Jung, C. Chen, R. Casellas, M.E. The study enrolled more than 2,100 actively suppressing the immune response. Ward, and A. Nussenzweig, Nature 2021; nonsmoking women from racially and The researchers created genetically DOI.:10.1038/s41586-021-03468-5) ethnically diverse backgrounds with no history engineered myeloid cells (GEMys) that produce [BY CHARLESICE GRABLE-HAWKINS, OD] of health problems. They reported their daily interleukin 12 (IL-12). The mice treated with consumption of caffeinated beverages and GEMys had decreased metastatic cancer NIAID: NEW WAY TO TEST TREATMENTS FOR provided a blood sample between 10 and 13 and muscle-tumor size and lived longer than DEADLY BRAIN DISEASE weeks of pregnancy. Compared with those control mice. GEMys in combination with other NIAID scientists have developed a new way to consuming minimal or no caffeine, women with treatments even prevented cancer recurrence. test treatments for Creutzfeldt-Jakob disease the highest plasma caffeine concentrations The team plans to test the safety of human (CJD), a fatal, incurable, neurodegenerative gave birth to babies that were 84 grams GEMys in a clinical trial of adults with cancer. brain disease caused by infectious prion lighter, 0.44 centimeters shorter, and had head (NIH authors: S. Kaczanowska, D.W. Beury, V. proteins. The lack of a human model to test circumferences 0.28 centimeters smaller. The Gopalan, A.K. Tycko, H. Qin, M.E. Clements, drugs for CJD has been a barrier to developing long-term implications are unclear, but caffeine J. Drake, C. Nwanze, M. Murgai, Z. Rae, W. Ju, treatments; studies in mice have failed to has been hypothesized to restrict blood supply K.A. Alexander, J. Kline, C.F. Contreras, K.M. identify antiprion compounds that were to the fetus, inhibiting growth, and potentially Wessel, S. Patel, S. Hannenhalli, M.C. Kelly, and ultimately effective in humans. putting infants at risk for childhood obesity and R.N. Kaplan, Cell 184:2033–2052.e21, 2021) chronic diseases later in life. (NIH authors: J.L. [BY LEANNE LOW, NIAID]

8 THE NIH CATALYST MAY–JUNE 2021 CATALYTICCATALYTIC RESEARCHRESEARCH

Gleason, F. Tekola-Ayele, R. Sundaram, S.N. efficacy against ST258, resistance against Hinkle, Y. Vafai, G.M. Buck Louis, M. Amyx, A.M. these drugs is expected to increase. Bever, M.M. Smarr, and K.L. Grantz, JAMA Netw The authors found that treating acute Open 4(3):e2132382021) sepsis with two phages (phage P1 and phage [BY SUBHASH VERMA, NCI] P2) that target ST258 improved survival:

Mice were first injected with ST258 to induce : NIAID CREDIT infection. They were then treated at several NIDA: ADOLESCENTS MAY DEVELOP different times after infection with phage P1, ADDICTIONS FASTER THAN YOUNG ADULTS phage P2, or both. Survival outcomes were NIDA researchers reported that the onset of dramatically improved from 0% in saline- NIAID: Bacteriophage treatment is effective against substance-use disorders (SUDs) is associated treated control mice to 100% in mice treated multidrug-resistant Klebsiella pneumoniae in mice. with the age an individual tried a drug for the Shown: Colorized scanning electron micrograph of with both phages. Early treatment combined K. pneumoniae interacting with a human neutrophil. first time. with using both phages resulted in the The scientists analyzed data from strongest recovery. Dagur, S. Yang, L.E.F. Almeida, Z.M. Quezado1, participants (ages 12–25 years) in the National The authors noted that although lower C. Combs, E.J. Lindberg, C.K.E. Bleck, J. Zhu, Surveys on Drug Use and Health, from 2015 bacterial concentrations were seen in the A.S. Shet, J.H. Chung, M. Pirooznia, and S.L. to 2018. They compared the prevalence of blood and tissues of the phage-treated mice, Thein, Blood 2020009063, 2021) substance use in adolescents (ages 12–17) and the recovered ST258 bacterium began to [BY BRANDI CAROFINO, NCI] in young adults (ages 18–25). Each group was demonstrate phage resistance. Further work examined at four intervals after their first use on the strategic selection of phages, phage of a drug: less than 12 months, 12–24 months, NIEHS: MOSQUITO PROTEIN MAY INHIBIT dosing, and engineering may improve the 24–36 months, and more than 36 months. The SOME DANGEROUS VIRUSES ability to predict therapeutic efficacy of phage study found that adolescents have a 10.7% The mosquito protein AEG12 strongly inhibits treatment in the future. (NIH authors: S. Hesse, chance of developing a SUD to cannabis within flaviviruses and weakly inhibits coronaviruses, N. Malachowa, A.R. Porter, B. Freedman., S.D. 12 months of their first experience, compared according to NIEHS scientists and their Kobayashi, D.J. Gardner., D.P. Scott, S. Adhya, with 6.4% in young adults. This difference collaborators. Flaviviruses cause yellow fever, and F.R. DeLeo, mBio 12:e00034-21, 2021) grew to 20.1% in adolescents and 10.9% in dengue, West Nile, and Zika, among other [BY EMMA ROWLEY, NIAID] young adults in the over-36-month interval. illnesses. Mosquitoes produce AEG12 when Similarly, an overall higher rate of SUDs were they take a blood meal or become infected found in adolescents with the misuse of NHLBI,CC: CIRCULATING MITOCHONDRIAL with flaviviruses. The researchers found that prescription drugs such as opioids, stimulants, DNA TRIGGERS INFLAMMATION IN SICKLE AEG12 destabilizes the viral envelope, but and tranquilizers. (NIH authors: N.D. Volkow, B. CELL DISEASE does not affect viruses without an envelope, Han, E.B. Einstein, and W.M. Compton, JAMA NIH researchers discovered that DNA from the such as those that cause pink eye and bladder Pediatr e206981, 2021) mitochondria triggers inflammation in people infections. AEG12 might also be effective [BY SATABDI NANDI, NIA] with sickle cell disease (SCD). The researchers against SARS-CoV-2, the coronavirus that identified elevated mitochondrial cell-free causes COVID-19, although it will take years DNA (cf-mtDNA) in the plasma of SCD patients of bioengineering to make AEG12 a viable NIAID, NCI: BACTERIOPHAGE TREATMENT compared with healthy control subjects. therapy. (NIH authors: A.C.Y. Foo, P.M. RESCUES MICE FROM MULTI-DRUG Normally, mature red blood cells do not contain Thompson, S.-H. Chen, B. Lupo, E.F. DeRose, S. RESISTANT KLEBSIELLA PNEUMONIAE mitochondria.These findings indicate that Arora, V.D. Placentra, L. Perera, L.C. Pedersen, Scientists from NIAID’s Rocky Mountain cf-mtDNA is not only a prognostic biomarker N. Martin, and G.A. Mueller, Proc Natl Acad Sci Laboratories (Hamilton, Montana) and NCI but may also contribute to the pathology of USA 118:e2019251118, 2021) have developed an effective therapy using SCD, opening new avenues for investigation [BY ROBIN ARNETTE, NIEHS] bacteriophages against multidrug-resistant and therapeutic intervention. (NIH authors: L. Klebsiella pneumoniae sequence type 258 Tumburu, S. Ghosh-Choudhary, F.T. Seifuddin, (ST258) in mice. The bacterium causes Read more, and longer, briefs at: https://irp. E.A. Barbu, S. Yang, M.M. Ahmad, L.H.W. high rates of mortality when left untreated. nih.gov/catalyst/v29i3/research-briefs. Wilkins, I. Tunc, I. Sivakumar, J.S. Nichols, P.K. Although newer antibiotics have shown

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

COVID-19 Timeline at NIH (March–April 2021)

medical treatments will be prioritized to receive transmission within and outside the body. (Nat a COVID-19 vaccine. Med, 2021; DOI:10.1038/s41591-021-01296-8) March 5: NIH Director Francis Collins updates March 26: NIH Director Francis Collins staff on the improving COVID-19 vaccine announces that 2,340 vaccine doses were supply; NIH received 2,400 Pfizer vaccine received to cover all phase 3 employees in second doses from the federal supply chain Maryland, as well as phase 4 employees who for Maryland-based employees. Additionally, are 75 and older. In addition, NIEHS in North the Montana Department of Public Health Carolina recieved 1,170 first and second doses and Human Services supplied 100 Moderna for staff. Collins also reports that NIH has had vaccine second doses for staff at NIAID’s Rocky its first case of a fully immunized staff member Mountain Labs (Hamilton, Montana). NIEHS in test positive for SARS-CoV-2 infection more North Carolina also received 230 first doses of than 14 days after the second dose. CREDIT: NIAID CREDIT: the Moderna vaccine. March 30: NIH announces that a NIAID-led Transmission electron micrograph of SARS-CoV-2 virus particles, isolated from a patient. Image captured and color- March 8: NIH launches the last of three clinical team found a largely intact immune response enhanced at the NIAID Integrated Research Facility (IRF) trials to evaluate the safety and efficacy of to three of the newly identified variants in in Fort Detrick, Maryland. the anticoagulant Eliquis to prevent life- recovered COVID-19 patients and vaccinated threatening blood clots. individuals. The study concludes that the SARS- March 1: An NIH-funded team launches a study March 10: NIH informs staff that HHS has CoV-2-specific CD8+ T-cells remain active and to assess an at-home COVID-19 testing system extended authorization for supervisors to offer protection against the emerging variants. paired with a smartphone app. approve excused absences for employees (Open Forum Infect Dis, 2021; DOI:10.1093/ofid/ March 1: NIH halts two ACTIV-3 clinical trial caring for dependents at home through ofab143) substudies for hospitalized patients. There September 10, 2021. March 31: The CDC and NIH launch an initiative were no safety concerns, but the Data and March 11: The one-year anniversary of the day called “Say Yes! COVID Test.” The program Safety Monitoring Board (DSMB) determined that the World Health Organization declared will provide free, rapid antigen tests to up to that there was a low likelihood of clinical value. the COVID-19 pandemic. 160,000 residents across two communities March 2: NIAID Director Anthony Fauci donates March 12: In his all-staff email, NIH Director in North Carolina and Tennessee. The effort his model of SARS-CoV-2 to the Smithsonian’s Francis Collins acknowledges that the past year aims to determine whether frequent, self- National Museum of American History. He has been a long and difficult one but shares the administered COVID-19 testing helps residents is awarded the museum’s Great Americans encouraging news that “nationally, COVID-19 reduce community transmission. Medal for his leadership during the COVID-19 case numbers are gradually dropping [and] March 31: NIAID and Moderna begin phase 1 pandemic and his lifetime work. more people are being vaccinated every day.” clinical trials to evaluate the effectiveness of a March 2: NICHD announces that it will lead a March 19: Francis Collins announces that all vaccine designed to protect against the B.1.351 research effort called “Collaboration to Assess Phase 3-eligible employees have been invited SARS-CoV-2 variant (the South African variant). Risk and Identify Long-term Outcomes for by Occupational Medical Services to schedule April 2: In his email to staff, Francis Collins Children with COVID (CARING for Children their COVID-19 vaccination appointments. announces that all NIH employees, including with COVID)”—to understand how SARS-CoV-2 March 22: Results from a large clinical teleworkers, are eligible to be vaccinated in affects children. trial, funded in part by NIAID, indicate that their communities under the classification March 2: NIH halts a clinical trial evaluating AstraZeneca’s COVID-19 vaccine, AZD1222, of essential health workers. He reports that the safety and effectiveness of COVID-19 is well-tolerated and protects against CDC announced results of a new agency convalescent plasma in treating emergency symptomatic COVID-19 disease including study providing strong evidence that mRNA department patients who had mild to moderate severe disease or hospitalization. COVID-19 vaccines, both Pfizer and Moderna, symptoms of COVID-19. The treatment was March 25: NIDCR-led study finds evidence are highly effective in preventing SARS-CoV-2 deemed unlikely to benefit these patients. that SARS-CoV-2 infects cells in the mouth. infection among health-care workers, first March 3: NIH Director Francis Collins announces The findings suggest that oral cells and saliva responders, and other essential workers. that employees scheduled for qualified urgent play a bigger role in SARS-CoV-2 infection than April 7: A new, NIAID-led clinical trial aims previously thought, and may contribute to to determine whether people who are highly

10 THE NIH CATALYST MAY–JUNE 2021 FEATURE

allergic or have a mast cell disorder are at April 14: NIH Director Francis Collins serves as increased risk for an immediate, systemic a panelist with colleagues from other medical allergic reaction to the Moderna or Pfizer- institutions during a virtual forum titled BioNTech vaccines. “Building Vaccine Confidence: Best Practices to April 8: NIAID Director Anthony Fauci Combat Misinformation and Vaccine Hesitancy and colleagues co-author a review article in COVID-19 Vaccines.” addressing the challenges posed by the COVID- April 15: A NIAID-sponsored clinical trial 19 and HIV pandemics. The authors conclude closes enrollment. The study was examining that accelerated development and clinical the efficacy of two drug combinations to testing of prevention and treatment strategies treat hospitalized patients with COVID-19 on are urgently needed to mitigate the dual supplementary oxygen. The DSMB determined pandemics. (J Infect Dis 2021; DOI:10.1093/ that neither treatment protocol studied is likely

infdis/jiab114) significantly better than the other. NIAID CREDIT: April 8: In his weekly email, NIH Director April 15: NIH announces that it is awarding up to Colorized scanning electron micrograph of an apoptotic cell Francis Collins expresses gratitude to all staff $33 million over two years to fund nationwide (green) heavily infected with SARS-COV-2 virus particles (purple), isolated from a patient sample. Image at the NIAID by performing a unique take on Beatles George projects that build evidence on safely returning Integrated Research Facility (IRF) in Fort Detrick, Maryland. Harrison’s “Here Comes the Sun.” students, teachers, and support staff to April 9: Francis Collins announces that NIH in-person school in areas with vulnerable and efficacy of two therapeutics for treating severe can now offer the COVID-19 vaccine to all underserved populations. COVID-19 in hospitalized patients. employees in phase 4 (staff on maximum April 16: NIH scientists find that the April 23: Participants begin enrolling at the telework) of the NIH vaccination plan. He experimental antiviral drug MK-4482 NIH Clinical Center for a new study assessing also shares that a research letter (authored significantly decreases viral particles and how people with immune-system deficiencies by NIAID researchers and others) reported disease damage in the lungs of hamsters respond to COVID-19 vaccination. interim results of a phase 3 trial of the Moderna treated for SARS-CoV-2 infection. MK-4482 is April 28: NIH Director Francis Collins testifies COVID-19 vaccine that found antibody activity now in phase 2 and 3 human clinical studies. before the House Energy and Commerce remained high in all age groups of a small study (Emerg Microbes Infect 9:2673–2684, 2020) Health Subcommittee on the impact of post- population at least 6 months after the second April 19: NIH announces it will provide $155 acute sequelae of COVID-19 (PASC), generally dose. (New Engl J Med 2021; DOI:10.1056/ million in funding for a large phase 3 clinical known as Long COVID. He highlights NIH’s new NEJMc2103916) trial to test several existing prescription and research initiative to better understand this April 9: President Joseph Biden’s budget over-the-counter medications that treat condition and find ways to treat or prevent it. proposal includes $51 billion for NIH (a $9 symptoms of COVID-19. The trial aims to April 29: NIH announces it will fund an billion increase over the 2021 enacted level). provide self-adminstered treatment options additional $29 million in grants for the NIH April 13: The Annals of Internal Medicine for adult patients with COVID-19 who have Community Engagement Alliance (CEAL) publishes a paper describing an NIAID-hosted mild-to-moderate symptoms and are not sick Against COVID-19 Disparities. The funding workshop where NIH experts discussed post- enough to be hospitalized. will bolster research to help communities acute COVID-19. (Ann of Intern Med 2021; April 21: A NIAID-sponsored phase 2 and disproportionately affected by COVID-19. DOI:10.7326/M21-1043) 3 clinical trial launches to evaluate a new April 30: In his email message to staff, NIH April 13: A NIAID-funded clinical trial begins antibody used to treat SARS-CoV-2. Called Director Francis Collins reports that over 60% testing an investigational monoclonal antibody SAB-185, the therapeutic is made from of NIH employees have been vaccinated against to treat patients with COVID-19 who are polyclonal human immune cells and will be COVID-19. He calls attention to a new study of hospitalized with respiratory disease. tested on non-hospitalized people with mild or the Pfizer and Moderna mRNA vaccines that April 13: The FDA and CDC initiate a pause moderate cases of COVID-19. found fully vaccinated adults 65 years and on the use of Johnson & Johnson COVID-19 April 22: Other trials for therapeutics that treat older, who are among the most vulnerable vaccine due to an exceedingly rare blood COVID-19 are underway this week. A phase 3 groups, were 94% less likely to be hospitalized clotting disorder reported in six cases. The clinical trial, supported by NIAID and NHLBI, than their unvaccinated counterparts. pause is lifted on April 23. has begun enrollment to test the safety and

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

Life in Outer Space CONTINUED FROM PAGE 1

gravity as a constant frame of reference to inform its sense of balance. The brain loses this reference after a person spends a long time in space or on the ISS, so astronauts have a very poor sense of balance when they return to Earth. Both issues are temporary, but could be detrimental when landing in a new environment such as Mars. If you can’t see or move very well, avoiding dangerous situations would be difficult. Space travel can also affect mental health. Astronauts on the ISS, Shelhamer

CREDIT: NASA CREDIT: pointed out, reported increased stress

This artist’s concept depicts astronauts and human habitats on Mars. NASA’s Mars 2020 rover will carry a number of during a six-month study conducted technologies that could make Mars safer and easier to explore for humans. by researchers at the University of Pennsylvania (Philadelphia). Even though some astronauts may “thrive on and Christopher Wanjek explained in be out of luck. [stress], it still may be impacting them their virtual Demystifying Medicine To illustrate that point, Shelhamer physiologically,” said Shelhamer. There lecture on February 23rd. described a medical emergency that may be “alternations in immune system Shelhamer, a professor of occurred on the International Space function and cardiovascular function.” otolaryngology at Johns Hopkins School Station (ISS) a couple of years ago: An That stress, along with other perils, such of Medicine (Baltimore) and former chief unidentified astronaut had a blood clot as radiation exposure, can be dangerous. scientist of the Human Research Program in their neck. Although there was no “The thing that really [keeps] me up at at NASA, is studying sensorimotor established method for treating them in night is the thing we haven’t thought physiology, with an emphasis on vestibular a microgravity environment, the ISS did of,” said Shelhamer. “It’s the funny and oculomotor systems, and how have a small supply of blood thinners on combination of things that happen that astronauts adapt to space flight and living board. A doctor on Earth advised NASA we have no way of predicting.” in space. In particular he is interested how to ration the medication until the Shelhamer believes that a broad in how weightlessness affects vision and next cargo mission could bring more integrative approach that assesses medical, balance. medication to the ISS. The astronaut was physiological, and psychological issues is Wanjek, a health and science treated successfully and survived. What a good way to maintain physiological and journalist who writes regularly about if the same dilemma arose on a trip to psychological fitness for long-duration astronomy and previously worked at Mars, or on Mars itself? Earth wouldn’t space flights and life in outer space. NASA, described the psychological and be able resupply the mission as easily. When humans have made it to physical challenges of traveling in space Both Wanjek and Shelhamer Mars safely, what other hazards may and settling on another planet. described other health issues associated await? The sun poses far more risk on A major risk of living in space or on with living in a near-zero-gravity Mars than on Earth, the speakers said. another planet is having to survive without environment including reduced bone Earth’s atmosphere is thick enough that relying on Earth. Earth is more than 140 density and muscle tone, and a shift sunscreen is sufficient protection against million miles—and seven months of space of fluids upward that increases volume the sun’s harmful rays. With the thinner travel—away from Mars. If an emergency and pressure in the head. For example, Martian atmosphere, a little sunbathing occurred on a mission to Mars or another Shelhamer explained, vision is affected as would expose humans to life-threatening planet, such as running out of supplies or the eyes become slightly flattened and the amounts of radiation. What’s more, having a medical crisis, the crew would retina swells. What’s more, our brains use the Martian soil contains perchlorates,

12 THE NIH CATALYST MAY–JUNE 2021 FEATURE FROM THE ANNALS OF NIH HISTORY

Walter Thomas chemicals poisonous to humans. You by lush trees. “I mean, look at this one; it Lingenfelter certainly wouldn’t want to grow potatoes has patio furniture,” he said, “Wouldn’t in that soil as Matt Damon’s character in you want to live here [rather] than in some (1948–2021) the movie The Martian did. ice-fishing hut on Europa?” BY MICHELE LYONS, OD Mars may have a hostile environment, In 1954, six-year-old “Tommy” but some workarounds are possible, To view the videocast of the February Lingenfelter visited the NIH Clinical Wanjek explained. For instance, we could 23, 2021, Demystifying Medicine lecture Center to have his heart evaluated by live in caves for radiation protection and “Biomedical Challenges in Space,” go to the National Heart, Lung, and Blood use aquaponics with light-emitting diodes https://videocast.nih.gov/watch=41287. Institute’s (NHLBI’s) cardiac-surgery to grow plants and raise fish. For Demystifying Medicine’s full schedule team. His parents were told that he Still, we have much to learn about and links to past lectures, go to https:// might not live past 18 years old. But after what it would take to be sure people could demystifyingmedicine.od.nih.gov. two successful heart-valve replacement safely live on another planet. What would surgeries—one in 1958 and another in be the long-term effects of living in a Megan Kalomiris, a postbaccalaureate fellow 2006—and a long-lasting association microgravity environment? Could humans in the Laboratory of Infectious Diseases with NIH, he lived more than 50 years give birth to and raise healthy children in the National Institute of Allergy and beyond what was expected. He had three in a space colony? Can Mars sustain a Infectious Diseases, studies noroviruses. sons and five grandchildren, too. Sadly, natural human settlement? After completing her NIH training in Walter Thomas Lingenfelter died on Wanjek concluded his talk by raising 2021, she will be attending the Science March 2, 2021, just a few weeks shy of an alternative possibility of living above Communications Master’s Program at the his 73rd birthday. planets—“in orbiting spheres [with] University of California at Santa Cruz When I heard the news about his artificial climate with climate control (Santa Cruz, California). In her spare passing, memories came flooding back. with perfect gravity”—and visiting planets time, she enjoys taking walks in the woods I remembered first meeting him in 2009 from there. He displayed a concept image and playing games (now, virtually) with to talk about the NIH Stetten Museum’s showing modern architecture surrounded her friends. plans for an exhibit on NIH’s role in the development of prosthetic heart valves. I was sitting in the Clinical Center lobby looking for an old man, but I didn’t see one. Finally I noticed someone who looked like Elvis. It dawned on me that this was Lingenfelter. He greeted me with a hearty handshake and said “Call me Link.” Link had had many health problems from the time he was a baby and had been to countless hospitals. No one could figure out what was wrong until a country doctor realized Link had a heart defect and referred him to the NHLBI cardiac-surgery team, one of the best in the country and led by Andrew Glenn Morrow. The last time I saw Link was in 2019. He was still the cheerful, energetic Link that I had come to know. CREDIT: NASA/RICK GUIDICE CREDIT: Space colonies: Artist’s rendering of a cutaway view of NASA’s proposed Stanford torus design. This space habitat would be capable of housing 10,000 to 140,000 people; have a comfortable, artificial climate; would rotate to produce artificial Read more online: https://irp.nih.gov/catalyst/ gravity; and have a system of mirrors that would provide sunlight and solar energy. v29i3/from-the-annals-of-nih-history.

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

Searching For Answers NIH’s Undiagnosed Diseases Program Grows Into a Worldwide Model BY MICHAEL TABASKO, OD

to treatments,” he said. Then, two things happened that propelled the UDP beyond Gahl’s expectations. First, in May 2008, then–NIH Director Elias Zerhouni and other NIH leaders held a press teleconference to announce the UDP. In addition to reporters, representatives from 96 rare-disease organizations were on the phone. “After that, the applications started pouring in,” said Gahl. Second, next-generation sequencing (NGS) was burgeoning at the time. NGS allowed an entire human genome to be sequenced in a single day instead of years. In addition, whole-exome sequencing (focused on protein-coding regions of DNA) now allowed researchers to selectively search for CREDIT: HTTPS://WWW.YOUTUBE.COM/WATCH?V=MCVWGEHA1FK CREDIT: mutations in a patient’s genetic code that None of Zarko Stanacev’s physicians could figure out what was causing attacks that rendered him nearly comatose, could be causing their symptoms. confined him to a wheelchair, and cloaked him in profound fatigue. NIH’S Undiagnosed Diseases Program, however, found a mutation in the NLRP3 gene that was causing abnormal inflammation in his body. Hours after being given a NIH’s laboratories are also certified by drug to treat inflammation, he dramatically improved and was up and walking without pain. Pictured: Zarko Stanacev the Centers for Medicare and Medicaid (sitting) and NHGRI neurologist Camilo Toro (standing) who led the team that treated Stanacev. Services through the Clinical Laboratory Improvement Amendments. The Zarko Stanacev had suffered a drug used to treat inflammation, he certification was a costly but necessary debilitating symptoms for more than a dramatically improved and was up and distinction for a lab’s results to influence decade. What started out as episodes of walking without pain. Finally, he had hope a patient’s care. In 2008, however, there hearing loss and severe headaches escalated and a path back to a normal life. was no CLIA certification anywhere for to periodic seizures and meningitis. The For many patients, the UDP represents whole-exome sequencing. Therefore, UDP attacks rendered him nearly comatose, their last, best hope. The UDP is a trans- investigators performed the test on a research confined him to a wheelchair at times, NIH initiative hosted by NHGRI. UDP basis to detect genetic mutations. Then those and cloaked him in profound fatigue. His Director William Gahl started the program results were individually certified to confirm medical providers were mystified. Without in 2008 with $280,000 of funding from the each patient’s variant(s). answers, the prospect of his living a normal Office of Rare Diseases Research (ORDR). Three weeks after the press conference, life seemed out of reach. “Steve Groft, director of the ORDR Gahl sat at his desk staring at an eight- But in 2017, Stanacev was accepted into at the time, was getting calls from patients inch stack of medical charts. “I remember NIH’s Undiagnosed Diseases Program whose diseases had no name,” said Gahl. thinking, what did I just get myself into?” (UDP), where an interdisciplinary team “Clearly, there was an unmet need.” And he said. He leaned on the expertise and led by National Human Genome Research the UDP could meet that need. generosity of his colleagues across NIH. Institute (NHGRI) neurologist Camilo In the beginning, the UDP had only Since then, the growth of the UDP has Toro set out to discover the source of his a staff of four: Gahl, a scheduler, and two been nothing short of remarkable. The puzzling symptoms. They found a mutation nurse practitioners. “I expected we would program has received more than 4,000 in the NLRP3 gene that was causing answer a few people’s questions, do some medical records; admitted 1,300 patients abnormal inflammation in Stanacev’s body. research in my lab on new diseases, perhaps (43% were children); sequenced 1,900 Hours after being treated with anakinra, discover new pathways which might apply exomes and 550 genomes; and made more

14 THE NIH CATALYST MAY–JUNE 2021 FEATURE CATALYTIC RESEARCH

NCI: HIGHER CANCER RISK CONTINUES AFTER CHERNOBYL than 316 diagnoses. And UDP scientists BY MICHAEL TABASKO have produced more than 180 publications. Young researchers have the opportunity In April 1986, the Chernobyl to work alongside seasoned investigators nuclear power plant accident in northern to discover new diseases. In 2011, clinical Ukraine exposed millions of people researchers identified the genetic cause of in the surrounding region to ionizing a rare and debilitating vascular disorder radiation, a known carcinogen. The associated with progressive and painful technology to study the genomic and calcification of arteries below the waist New( molecular effects on those exposed did Engl J Med 364:432–442, 2010). To date, not exist at the time. the UDP has discovered 23 new genetic Scientists from NCI led two disorders and disease phenotypes. international studies that shed new light Today, the UDP’s leadership consists of on how radiation exposure affects human Camilo Toro, lead neurologist and director NHGRI BARTLETT, MAGGIE CREDIT: DNA. The first study compared the genomes of the adult program; Cynthia Tifft, In 2008, William Gahl established the NIH Undiagnosed of 105 mother-father pairs who were exposed Diseases Program. Ever since it has been finding answers pediatric director; David Adams, attending to the most puzzling medical cases from around the world. to prolonged radiation after the Chernobyl pediatrician and director of bioinformatics; accident and their 130 adult offspring and May Malicdan, director of translational insurance to pay.” (born 1987–2002). Researchers found no research. The staff includes internists, The success of the UDP has had a increased incidence of de novo mutations. neurologists, bioinformatics specialists, and measurable impact. Insurance companies The findings offer reassurance that ionizing nurse practitioners. All are collaborating are beginning to cover the cost of genetic radiation exposure from the accident had a with specialists from across NIH. sequencing, not only for patients but for their minimal, if any, impact on the health of the Medical institutions across the country families as well. And, the establishment of subsequent generation. and all around the world have created UDPs throughout the globe demonstrates The second study used samples from the programs modeled after the UDP. In 2013, how an unmet need is finally being Chernobyl Tissue Bank to document genetic NIH expanded the program to form the recognized. changes in the tumors of 359 people who Undiagnosed Disease Network, now an Gahl hopes that someday, the UDP will developed thyroid cancer after being exposed extramural network of 12 clinical sites and be obsolete. “It’s always been our hope that as children or in utero and 81 unexposed supporting facilities throughout the United the program might need to be eliminated,” individuals born more than nine months States. By joining the network, the UDP has he said. “If there were no need for a program after the accident. A particular type of been able to draw extensive funding from like this, it would mean that the investigation DNA damage known as a double-strand the NIH Common Fund, creating stability of rare and new disease had been integrated break was strongly associated with radiation and support for the popular program. into our medical-health system.” dose, particularly for individuals exposed at Today, nearly half of UDP patients come a younger age. Furthermore, thyroid cancers to NIH with the results of their exome- The September–October 2010 of the in children exposed to higher radiation doses sequencing in hand. But what the program NIH Catalyst includes an article about were more likely the result of gene fusions, a provides continues to be unique. “We have the UDP’s beginnings: https://irp. type of mutation in which the wrong strands an unparalleled collection of experts here nih.gov/sites/default/files/catalyst/ of broken DNA are fused back together. at NIH that can discuss a case with their catalyst_v18i5.pdf. To learn more about (Study 1: Science, eabg2365, 2021; Study 2: colleagues,” Gahl said. “This process would the UDP, go to genome.gov/27544402/ Science, eabg2538, 2021) typically take one to two years [but] we can the-undiagnosed-diseases-program. do it in a week.” The treatments are free Read more at: https://irp.nih.gov/ to the patients. “We can order the tests Michael Tabasko is the science writer-editor for catalyst/v29i3/research-briefs-chernobyl. we think are needed without waiting for the NIH Catalyst.

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

Detecting and Fighting Transplant Rejection Profile: Sean Agbor-Enoh, M.D., Ph.D. BY ETHAN SMITH, NINR

Lung transplantation is a immune system. The patient has cfDNA complicated matter. On the one hand, it as well, but its genetic sequence is different offers healthy lungs and a second chance to than that of the ddcfDNA, which allows people with severe cystic fibrosis, chronic the two to be differentiated from each other obstructive pulmonary disease, pulmonary and quantified. Agbor-Enoh’s team has hypertension, or other diseases that cause found that ddcfDNA can detect transplant severe lung damage. On the other hand, rejection two to three months before a tissue organ rejection—a dangerous form of biopsy can. “It is very sensitive,” said Agbor- disease in which the transplant patient’s Enoh. “As soon as you start having a few own immune system attacks their donor cells in that organ dying, the cell-free DNA organ—is a major risk of a lung transplant. test is already positive.” About half of lung transplants fail within Currently, his team has found that five years, the highest failure rate of any cfDNA sampled during the early period transplanted organ. right after transplantation can predict This dilemma is something Sean Agbor- Sean Agbor-Enoh 80–85% of the patients who will develop Enoh knows very well. During his medical chronic rejection and die. In an article system down a notch, easing a transplant training, he became aware that the standard published in Circulation, Agbor-Enoh and into a recipient’s body. Still, 50–75% of method of detecting organ rejection—a colleagues sequenced the ddcfDNA of patients with transplant rejection die tissue biopsy—was problematic. By the time 165 heart-transplant patients (out of 171 within two years after starting standard a biopsy revealed that the organ was being participants). They found that cfDNA treatments using immunosuppressive drugs rejected, it was often too late to save the detects rejection 28 days before heart biopsy. such as rituximab, which work by binding lung. He has dedicated his career to finding Also, they estimated that by using cfDNA to and essentially nullifying the effect of the better ways to prevent organ-transplant as a biomarker, physicians can safely avoid transplant-targeting antibodies. rejection. Today, he is a tenure-track NIH 81% of invasive heart biopsies. While tissue Agbor-Enoh believes a large reason Lasker Clinical Research Scholar and an biopsies cost about $3,000–$3,500, the why patient outcomes are so poor is that NIH Distinguished Scholar at the National cfDNA test costs about $150 per sample. the “gold standard” for diagnosis, tissue Heart, Lung, and Blood Institute (NHLBI), biopsy, is flawed. For one thing, tissue where he heads the Lab of Applied Precision The Atlantic Coast of Cameroon biopsy is expensive and invasive. It involves Omics (APO). In the APO Lab, his Agbor-Enoh grew up in southwestern a surgical procedure to collect samples of research team is working to develop new Cameroon near Mount Fako, an active tissue from the transplant organ. But more ways to detect and treat transplant rejection. volcano on the Atlantic coast. Being “so importantly, tissue biopsy often detects The immune system can’t always close to nature…really stimulates a lot transplant rejection at an advanced stage of differentiate between the good intentions of questions in your mind,” he said. He the disease when treatment is potentially less of a lung transplant and the bad intentions never intended to become a doctor but effective. “The biopsy that we are using now of bacteria such as, for example, the life- wanted to study soil, petroleum chemicals is enabling us to detect [transplant rejection], threatening Clostridium difficile. Immune in particular. He had even been accepted but detect it late when [the disease] is very system activation results in a flurry of to a Ph.D. program in England, but his advanced,” said Agbor-Enoh. antibodies streaming through the blood family couldn’t afford the tuition. His father With Agbor-Enoh leading the APO vessels, ultimately latching onto the cells suggested his son attend medical school Lab, one of its main focuses is donor- that make up the transplant organ. The instead. In Cameroon, medical school was derived cell-free DNA (ddcfDNA), small resulting tissue damage leads to transplant a far less expensive option—at the time it strands of DNA that are released into the rejection, and eventually, organ failure. cost about $100 per year, some 1/500 the bloodstream by the donor organ when it Medicine draws on immunosuppressive cost of studying petrochemicals in England. is damaged by the transplant patient’s drugs to take the strength of the immune So, Agbor-Enoh went to the University of

16 THE NIH CATALYST MAY–JUNE 2021 FEATURE

Yaoundé (Yaoundé, Cameroon) to pursue pulmonary and critical care medicine at the will make [the test] more clinically feasible,” a medical degree. NIH Clinical Center (with Henry Masur) said Agbor-Enoh. In his fourth year of medical school, and Johns Hopkins Hospital. Getting the cfDNA test into the hands he volunteered for a World Health of clinicians also requires validation by other Organization program to help distribute Doctor Valantine is Calling labs in a large cohort of patients. Agbor- vaccines and medications in remote areas As Agbor-Enoh was finishing up the Enoh’s Scientific and Clinical Directors of Cameroon. He wound up in eastern fellowships, he received a phone call from Robert Balaban and Richard Childs Cameroon, an area without roads or Hannah Valantine, who was preparing to (NHLBI) have been great supporters. They hospitals. Sometimes, he had to walk move from the Stanford University School share his vision and provide the resources 8–10 hours to reach the villages where he of Medicine (Stanford, California) to NIH to support the Genomic Alliance for had to do his job with limited resources. to start a lab at NHLBI and become NIH’s Transplantation, which is a consortium of One day, he treated the son of a village first chief officer for Scientific Workplace NHLBI and several heart-lung transplant chief. The child likely had malaria and was Diversity. At Stanford, Valantine had already programs at hospitals in the Washington, dangerously anemic. “As I was holding the been working on repurposing cfDNA to D.C., area. The consortium’s goal is to do child and trying to figure out ways to get detect heart-transplant rejection. She asked the necessary studies to get cfDNA ready him to breathe, that child died,” said Agbor- whether he’d like to become a staff scientist for use in clinical care as quickly as possible. Enoh. “It is that experience that made me in her new transplantation genomics lab. Agbor-Enoh is planning clinical trials to commit to medicine. It made me go into He agreed on the spot and joined NHLBI test whether cfDNA will identify transplant research to try [to] solve problems, keep in 2015. rejection earlier than tissue biopsies can. people healthy—and alive.” Under Valantine’s mentorship, Agbor- Occasionally, Agbor-Enoh invites Enoh developed his own research mission, his lung-transplant patients to his lab Thinking in Parallels applied successfully to the Lasker Clinical meetings to share their stories about lung As Agbor-Enoh was starting his medical Research Scholars Program, and soon transplantation and transplant rejection. career, he was intrigued by the parallels started the APO Lab. In doing so, he hopes that the people in between the malaria parasite and an his lab “can continue to understand how organ transplant. Both malaria parasites Planning Ahead valuable their work is in improving the lives and transplanted organs have to adapt to The Agbor-Enoh Lab’s mission is to improve of these unfortunate patients for whom lung living in different environments in order lung-transplant survival by identifying and transplantation is the only cure.” to survive. “If the organ fails to adapt, addressing gaps in lung-transplant care. then the immune system of that host will As a first step, he is developing cfDNA To learn more about Sean Agbor-Enoh and his kill it,” he said. In addition, he noticed as a tool to detect transplant rejection. His work, visit the Office of NIH History’s “Behind the alarming rates at which transplant initial studies show that cfDNA only needs the Mask Project” interview at https://www. patients succumb to rejection. He saw a blood draw and detects rejection up to two youtube.com/watch?v=PqWryWkbo0o. transplantation medicine as a field with to three months before biopsy, the invasive To read a transcript of the interview, go to room for innovation and decided that it method that is currently used. Developing https://history.nih.gov/display/history/ would be the area to focus on. such a tool for clinical use has its challenges Agbor-Enoh%2C+Sean+2020. After completing medical school in and takes a lot of work. Currently, it takes 2002, Agbor-Enoh came to the United about a week and a half from the time the Ethan Smith is a postbaccalaureate fellow in States to pursue a Ph.D. in molecular biology sample is collected to the time the results Jessica Gill’s lab in the National Institute at Georgetown University Medical Center are ready. Agbor-Enoh is trying to leverage of Nursing Research. His research involves (Washington, D.C.), followed by an internal digital-droplet polymerase chain reaction studying biomarkers for traumatic brain medicine residency at Johns Hopkins to reduce the turnaround time of the test. injury. After completing his training at Bayview Medical Center (Baltimore). In “If you can fix the issue with methods…it NIH, he plans to apply to graduate pro- 2012, he began a joint clinical fellowship in grams in clinical psychology.

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

Recently Tenured

GRÉGOIRE ALTAN-BONNET, BEVIL CONWAY, NEI CARI KITAHARA, NCI-DCEG EROS LAZZERINI DENCHI, SUSAN M. LEA, NCI-CCR NCI-CCR NCI-CCR

GRÉGOIRE ALTAN-BONNET, PH.D., NCI-CCR and quantitative understanding to propel BEVIL CONWAY, PH.D., NEI Senior Investigator and Head, the personalization, optimization, and Senior Investigator, Sensation, Cognition, ImmunoDynamics Group, Laboratory of generalization of cancer immunotherapies and Action Section, National Eye Institute Integrative Cancer Immunology, Center for to all cancer patients. Education: McGill University, Montreal (B.Sc. Cancer Research, National Cancer Institute My group is developing experimentally in biology); Harvard Medical School, Boston Education: École Normale Supérieure, Paris validated quantitative models of the immune (M.M.Sc.); Harvard University, Cambridge, (B.S. and M.S. in physics); The Rockefeller response—from signaling responses, to Massachusetts (Ph.D. in neurobiology) University, New York (Ph.D. in physics) antigens and cytokines, to differentiation Training: Postdoctoral training at Harvard Training: Postdoctoral fellow, Laboratory of and proliferation of leukocytes, to killing Medical School Immunology, National Institute of Allergy of tumors. We engineered a novel robotic Before coming to NIH: Associate professor in and Infectious Diseases (2000–2005) cell-culture system to map the combinatorial neuroscience, Wellesley College (Wellesley, Before returning to NIH: Associate member and dynamic complexity of leukocyte Massachusetts) and principal research of Computational Biology and Immunology, activation. We have also developed new scientist at Massachusetts Institute of Memorial Sloan-Kettering Cancer Center quantitative methods, machine learning, Technology (Cambridge, Massachusetts) (New York) and computational modeling to identify Came to NIH: In 2016 Came to NIH: In 2000–2005 for postdoctoral hallmarks of successful immunotherapies Outside interests: He is a visual artist. training; returned in 2015 as an Earl Stadtman (Science 370:1328–1334, 2020). Website: https://irp.nih.gov/pi/bevil-conway Investigator in NCI Our current projects involve the Outside interests: Hiking; sailing; cooking; multicellular coordination of immune Research interests: My group investigates having dinner parties (when pandemic over) responses against tumors and pathogenic the neural basis for visual perception Website: https://irp.nih.gov/pi/ infections. In collaboration with Nihal and uses color as a model system for gregoire-altan-bonnet Altan-Bonnet’s group at NHLBI, we exploring how the brain processes sensory investigated how beta-coronaviruses— information. To better understand how the Research Interests: Thanks to the including SARS-CoV2, which causes brain enables us to recognize faces, colors, pioneering work of Steve Rosenberg, COVID-19—use lysosomes to leave cells objects, and places, my lab uses functional colleagues in NCI’s intramural program, instead of biosynthetic secretory pathways. magnetic-resonance imaging (fMRI) and others from all over the world, scientists Such highjacking of lysosomes by beta- and magnetoencephalography in human have been able to harness the power of the coronaviruses explains some of the immune participants. These techniques use sensors immune system to attack tumors. The abnormalities observed in COVID-19 around the head to noninvasively record past 20 years have seen a flurry of novel patients (Cell 183:1520–1535.e14, 2020). Our blood-flow changes and tiny magnetic approaches in cancer immunotherapy continued efforts will help develop tailored fields brought about by brain activity. The to boost leukocyte activation and tumor immunotherapies against such pathogenic lab also does experiments in animal models eradication. Yet we are lacking a systematic infections and tumors.

18 THE NIH CATALYST MAY–JUNE 2021 COLLEAGUES

SUNG-YUN PAI, NCI-CCR UDO RUDLOFF, NCI-CCR LEOREY N. SALIGAN, NINR LEI SHI, PH.D., NIDA

to understand at a cellular and network level globe name colors (Proc Natl Acad Sci U Research interests: My research focuses on how the brain works. S A 114:10785–10790, 2017). In a third 1) cancer risks in people—medical personnel Our work is organized around set of studies, we determined the color as well as patients—who are exposed to three broad approaches: 1) using fMRI information carried by cells in the brain diagnostic and therapeutic radiation and 2) in humans and nonhuman primates that are responsible for face recognition the etiology of thyroid cancer, which is one (NHPs) to investigate homologies of to test ideas about how the brain detects of the most radiosensitive tumors. brain anatomy and function among these health and emotions of others. (eNeuro 2021; Within the U.S. Radiologic species and to test hypotheses about the DOI:10.1523/ENEURO.0395-20.2020) Technologists Study, the largest cohort fundamental organizational plan of the and Nat Commun 10:3010, 2019). of radiologic technologists in the world, cerebral cortex in the primate; 2) using And finally, our team recently used I demonstrated that medical staff who microelectrode recording in NHPs to show brain imaging to decode what colors people perform nuclear medicine procedures and on a mechanistic level how populations of see. The study also revealed correlations fluoroscopically guided interventional neurons drive behaviors such as perceptual between neurological signals and patterns procedures receive doses of radiation that decisions and categorization; and 3) doing in color naming. (Curr Biol 31:1–12, 2020) are several times as high as those performing comparative psychophysical studies in general radiologic procedures. Increased humans and NHPs as part of a program doses are associated with adverse health of neuroethology to understand the relative CARI KITAHARA, PH.D., NCI-DCEG outcomes. These findings led to efforts to computational goals of perception and Senior Investigator, Radiation Epidemiology reinforce and improve personal protective cognition in different primate species. Branch, Division of Cancer Epidemiology equipment and occupational monitoring, In addition to studies of vision, my team and Genetics, National Cancer Institute and to informed regulatory decisions for conducts experiments using auditory and Education: University of Michigan, Ann occupational dose limits in the United combined audiovisual stimuli to understand Arbor, Michigan (B.S. in biology and States. common principles of sensory-cognitive anthropology/zoology); Johns Hopkins I also investigate risks to patients from information processing, and to determine Bloomberg School of Public Health, nuclear medicine procedures. I led an how signals across the senses are integrated Baltimore (M.H.S. and Ph.D. in cancer international effort to extend the follow- into a coherent experience. In recent work epidemiology) up of the largest international cohort of we discovered a substantial difference in Training: Postdoctoral training at NCI-DCEG patients with hyperthyroidism. My analysis how macaque monkey (Macaca mulatta) Came to NIH: In 2007 for training; became a of those data resulted in a report establishing and human brains process auditory-pitch tenure track investigator in 2015 that radioactive iodine treatment increases information (Nat Neurosci 22:1057–1060, Outside interests: Playing with her two cancer risks in these patients (JAMA Intern 2019; DOI:10.1038/s41593-019-0410-7). boys (ages 3 and 6); riding her Peloton bike; Med 179:1034–1042, 2019). Because of Other studies uncovered a universal traveling (except during a pandemic) the potential for influencing treatment pattern in how languages across the Website: https://irp.nih.gov/pi/cari-kitahara CONTINUED ON PAGE 20

https://irp.nih.gov/catalyst 19 COLLEAGUES

Recently Tenured CONTINUED FROM PAGE 19 recommendations and patient preferences, role in preventing the activation of the DNA Before coming to NIH: Chair of Microbiology, my findings have been widely discussed by damage-response pathway and suppression Sir William Dunn School of Pathology, medical professional societies and clinical of end-to-end chromosomal fusions. University of Oxford; Scientific Director, guidelines committees. A complementary study in our lab is Central Oxford Structural Microscopy and My descriptive research has shown focused on the in vivo consequences of Imaging Centre (Oxford) rising trends in the incidence of advanced telomere dysfunction. Telomere length Came to NIH: December 2020 thyroid cancer and thyroid cancer–specific homeostasis plays a critical role in cellular Outside interests: Listening to Baroque mortality, providing support for a true and organism survival. However, in humans, music; hiking; cooking increase in the disease in the United States this process is inefficient, and progressive Website: https://irp.nih.gov/pi/susan-lea (JAMA 317:1338–1348, 2017). My etiologic telomere shortening is observed in tissues research, which focuses on large cohort with a high cellular turnover. In the lab, Research interests: As a structural studies and international consortia, has we probe the role of telomere shortening in biologist, I have pioneered the use of mixed helped to establish obesity as a modifiable aging and tumor onset using mouse models structural methods to study host-pathogen risk factor for thyroid cancer and as an that recapitulate telomere dysfunction in interactions and other medically important important contributor to the rising incidence. stem cells and other cellular compartments. molecular pathways. My laboratory uses and Our most recent work revealed that develops cutting-edge structural methods embryonic stem cells could survive and including cryoelectron microscopy and EROS LAZZERINI DENCHI, PH.D., NCI-CCR proliferate in the absence of proteins that X-ray crystallography to define molecular Senior Investigator and Head, Telomere are usually essential for telomere protection. mechanisms involved in health and disease. Biology Unit, Laboratory of Genome In this work, we found that embryonic stem My lab is focusing on different biological Integrity, Center for Cancer Research, cells possess an alternative mechanism systems ranging from bacterial pathogenesis National Cancer Institute of telomere protection triggered by the to human cell division. We are looking at Education: University of Milan, Milan, Italy induction of genes typically used only how large, multiprotein complexes, often (B.S. and M.S. in biology); European Institute during the earliest stage of development membrane-crossing, are assembled. In of Oncology, Milan (Ph.D. in molecular to stave off unwanted DNA repair. These our bacterial pathogenesis studies, we oncology) findings reported on November 25, 2020, often examine the large membrane- Training: Postdoctoral fellow at Rockefeller in Nature (Nature 589:110–115, 2021) might spanning complexes involved in bacterial University (New York) help explain the survival strategy used by movement and the secretion of bacterial Before coming to NIH: Associate professor, some cancer cells to circumvent growth proteins and toxins. In our research on Department of Molecular Medicine, The limits imposed by the natural shortening human systems, we examine how serum- Scripps Research Institute (La Jolla, of telomeres that occurs as we age. resident protein cascades act in immune California) responses and coagulation; how centrosomes Came to NIH: In 2018 as a Stadtman assemble during mitosis; and how a Investigator; became tenured as a senior SUSAN M. LEA, D.PHIL., F.MED.SCI., NCI-CCR variety of membrane proteins function investigator in March 2021 Senior Investigator and Chief, Center for in protein and membrane maturation, as Outside interests: Sailing and cycling Structural Biology, Center for Cancer Research, transporters or cellular receptors. We use Website: https://irp.nih.gov/pi/ National Cancer Institute multiple biophysical methods to address the eros-lazzerini-denchi Education: University of Oxford, Oxford, questions we pose about these challenging England (B.A in physiological sciences; D.Phil. systems, and we often develop software and Research interests: Chromosome endcaps, in molecular biophysics); elected Fellow of the experimental methods to allow us to obtain called telomeres, shorten as one ages. I am United Kingdom Academy of Medical Sciences the answers we seek. interested in the mechanisms by which (F.Med.Sci.) We have spent many years trying telomeres protect chromosome ends Training: Postdoctoral training, Laboratory of to understand the atomic details of the and their deregulation in aging and in Molecular Biophysics, University of Oxford, bacterial flagellum, the long appendage pathologies such as cancer. My lab studies and at Linacre College (Oxford) that many bacteria need to move through telomere-associated proteins to define their a fluid environment and cause disease. A

20 THE NIH CATALYST MAY–JUNE 2021 COLLEAGUES

flagellum is a multiprotein motor powered Outside interests: Spending time with family; outcome. My team is also working on by the movement of ions across the bacterial cooking; playing flute; reading both fiction developing cellular therapies for Wiskott- membrane, an incredibly complex protein and nonfiction Aldrich syndrome and deficiency of nanomachine. Our recent work has Website: https://ccr.cancer.gov/idctp/ dedicator of cytokinesis protein 8. illuminated many previously unknown sung-yun-pai aspects of the machine and has revealed how the bacteria tightly intermesh the Research interests: I am developing UDO RUDLOFF, M.D., PH.D., NCI-CCR protein components with the membrane and testing tailored cellular therapies, Senior Investigator, Rare Tumor Initiative, itself to contain the rapidly rotating motor. including allogeneic hematopoietic stem-cell Pediatric Oncology Branch, Center for Building a clearer picture of these disease- transplantation (for example, bone-marrow Cancer Research, National Cancer Institute causing machines will open opportunities transplant) and gene therapy, for children Education: Ruprecht Karls University School for novel antibacterial agents in this age and adults who have genetic diseases of of Medicine of Heidelberg, Heidelberg, of antibiotic resistance. (References for the blood and immune system. One of Germany (M.D., Ph.D.) research: 1) Accepted Nat Microbiol, my goals is to understand how individual Training: Residency in obstetrics and bioRxiv 2020.12.05.413195, 2020; 2) genes and the type of chemotherapy given gynecology at several different teaching Nat Microbiol 5:1553–1564, 2020; 3) Nat before cellular therapy influences immune hospitals in England; residency in general Microbiol 5:966–975, 2020; DOI:10.1038/ reconstitution. surgery, New York University School of s41564-020-0703-3) Babies with severe combined Medicine and Albert Einstein College of immunodeficiency (SCID) are born Medicine (New York); fellowship in surgical without T lymphocytes and typically die oncology, Memorial Sloan-Kettering Cancer SUNG-YUN PAI, M.D., NCI-CCR in infancy without cellular treatment. I led Center (New York) Senior Investigator and Chief, Immune a multi-institutional study with the Primary Came to NIH: In 2009 as tenure-track Deficiency Cellular Therapy Program, Immune Deficiency Treatment Consortium investigator in NCI-CCR, first in the Surgery Center for Cancer Research, National showing that giving SCID patients Branch (2009–2013), then in the Thoracic Cancer Institute transplants before the onset of infection was and GI Oncology Branch (2013–2018) and Education: Harvard College, Cambridge, critical to survival, that some types of SCID Rare Tumor Initiative, Pediatric Oncology Massachusetts (B.A. in East Asian languages have better immune correction than others, Branch (2018–present) and civilization); Harvard Medical School, and that using chemotherapy improves Outside interests: Spending time with Boston (M.D.) correction of the immune system (N Engl his nine-year-old daughter; reading; Training: Residency in pediatrics, Boston J Med 371:434–446, 2014). This study and volunteering for the German-American Children’s Hospital (Boston); clinical other work underlie the open trial I am Heritage Foundation; hiking fellowship in pediatric hematology/oncology, leading at more than 40 institutions that Website: https://irp.nih.gov/pi/udo-rudloff Boston Children’s Hospital and Dana- involve randomizing patients with SCID Farber Cancer Institute (Boston); research to either of two chemotherapy regimens. Research interests: My laboratory fellowship in rheumatology and allergy Autologous gene therapy uses the concentrates on the discovery, translation, immunology, Brigham and Women’s Hospital patients’ own cells, representing the ultimate and early-phase clinical testing of novel (Boston) personalized treatment. We re-engineered therapies for patients with pancreatic or other Before coming to NIH: Associate professor a viral vector that was successful in treating solid-organ cancers. We have built a program in pediatrics, Harvard Medical School; the X-linked form of SCID but caused that integrates phenotype-directed drug attending physician at Boston Children’s leukemia. We showed in a clinical trial screening with target deconvolution (the Hospital and Dana-Farber Cancer Institute, that the new vector was just as effective process of identifying the molecular targets and co-director of the Gene Therapy and safer, with no leukemias to date after 10 of active hits) and translational science to Program, Boston Children’s Hospital and years (N Engl J Med 371:1407–1417, 2014). arrive at drug candidates that target novel Dana-Farber Cancer Institute We now have a multi-institutional trial of essential mechanisms of cancer and yield Came to NIH: In 2020 gene therapy for this disease using low- CONTINUED ON PAGE 22 dose busulfan to further improve immune

https://irp.nih.gov/catalyst 21 COLLEAGUES

Recently Tenured CONTINUED FROM PAGE 21 candidates with favorable pharmacokinetic patent for “Small Molecules with Selective Research interests: I am exploring the and toxicokinetic properties. Activity Against the M2 Phenotype of nature and causes of fatigue in relation I led efforts for the preclinical and Macrophages.” to cancer and its treatments. Fatigue is a clinical development of the first-in- We have also found that pancreatic common and debilitating condition that class, small-molecule metarrestin, which tumors with KRAS G12R mutations affects most cancer patients, impairing suppresses metastasis in pancreatic cancer (present in 15–18% of pancreatic cancers) their health-related quality of life. To date, and other solid-organ cancers. Metarrestin show increased response to the MEK fatigue remains poorly characterized with targets the perinucleolar compartment, inhibitor selumetinib in preclinical models. no diagnostic test to objectively measure which is associated with the ability of cancer (Cancer Discov 10:104–123, 2020). A phase the severity of this condition. In addition, cells to metastasize. Orally administered 2 clinical trial, however, did not show tumor evidence has shown that the biology of metarrestin has favorable bioavailability regressions in patients with advanced cancer-related fatigue (CRF) is complex, and biodistribution across different species, pancreatic cancer who were treated with and the condition may be caused by a achieves high intratumoral exposure a single-agent MEK inhibitor. We are cascade of biologic events in response to concentrations, and has a predictable toxicity currently evaluating, preclinically, the best cancer and its treatments. profile. We are enrolling patients in a first- possible MEK combination therapy for this Acknowledging the individual in-human phase 1 study of metarrestin (Sci patient subpopulation. variabilities in CRF, even among patients Transl Med 10:441–455, 2018). receiving similar treatments and having A second drug-discovery program the same disease condition, my team focuses on tumor-associated macrophages, LEOREY N. SALIGAN, PH.D., R.N., C.R.N.P., observed that only a subpopulation of a major pro-tumor immune-cell population F.A.A.N., NINR patients experience chronic fatigue after in many solid-organ cancers. Tumors Senior Investigator, Symptoms Biology Unit, completing primary cancer treatment. The typically co-opt macrophages to promote and Acting Chief, Symptom Science Center, individual susceptibility to activate specific tumor growth and evasion from immune National Institute of Nursing Research glutamate receptors seems to have a role surveillance. In pancreatic cancer models, Education: Silliman University, Dumaguete in the chronic fatigue of a specific group we found that the first-in-class synthetic City, Philippines (B.S in medical technology); of cancer patients months after completing host-defense peptide design RP-182 Liceo de Cagayan University, Cagayan de their primary treatment. (Transl Psychiatry improved responses to chemotherapy and Oro, Philippines (B.S. in nursing); Hampton 8:article number 110, 2018). We used this checkpoint blockades by binding to the University, Hampton, Virginia (M.S. and Ph.D. discovery to conduct a proof-of-concept innate immune checkpoint CD206 and in family nursing) clinical trial to investigate the antifatigue targeting CD206-positive matrix-2 (M2)- Training: Postdoctoral fellow, Pain Research effects of inhibiting glutamate receptors like tumor-associated macrophages. (Sci Unit, NINR using low-dose ketamine. This study is Transl Med 12(530):eaax6337, 2019). RP-182 Before coming to NIH: Nurse practitioner, actively enrolling participants. reprograms tumor-associated macrophages pulmonary and critical care specialist Recently, my group also found that and increases cancer-cell phagocytosis and (Norfolk, Virginia); faculty, Family Nurse cancer survivors carrying a specific antitumor immune responses in various Practitioner Program, School of Nursing, Old polymorphism (Val66Met) of their brain- cancer models. Through several in silico Dominion University (Norfolk) derived neurotrophic factor (BDNF) (computer simulation), medicinal-chemistry, Came to NIH: In 2006 as nurse practitioner gene experienced less fatigue. Although and structural-biology approaches we have in NEI; did postdoctoral training in NINR’s Val66Met has been shown to greatly recently replaced RP-182 with another Pain Research Unit (2007–2009); became increase the risk for depression in healthy small-molecule design that has improved associate clinical investigator in NINR in individuals, it did not affect depression pharmacokinetic features and is yielding 2009; became tenure-track investigator in symptoms in these cancer survivors (Transl a drug candidate for advanced preclinical 2012 Psychiatry 10:article number 302, 2020). studies. Outside interests: Running; traveling This is an interesting discovery, considering We have been issued a patent for Website: https://irp.nih.gov/pi/ that fatigue has always been associated “Peptide-Based Methods for Treating leorey-saligan with depressed mood. Using a mouse Pancreatic Cancer” and a provisional

22 THE NIH CATALYST MAY–JUNE 2021 NIH ABBREVIATIONS COLLEAGUES CBER: Center for Biologics Evaluation and Research, FDA CC: NIH Clinical Center CCR: Center for Cancer Research, NCI CIT: Center for Information Technology DCEG: Division of Cancer Epidemiology and model, my team is exploring the unique and the lipid environment. The integrated Genetics, NCI brain networks associated with this specific findings allow us to rationally develop DIPHR: Division of Intramural Population BDNF polymorphism to help us understand small-molecule compounds for novel drug Health Research, NICHD FAES: Foundation for Advanced Education how fatigue is perceived and experienced. discovery. in the Sciences Specifically, for G-protein-coupled FARE: Fellows Award for Research Excellence receptors, our findings delineate the FelCom: Fellows Committee LEI SHI, PH.D., NIDA FDA: Food and Drug Administration structural determinants of ligand selectivity FNIH: Foundation for the NIH Senior Investigator and Chief, and efficacy for dopamine receptors FNL: Frederick National Laboratory Computational Chemistry and Molecular from both protein and small-compound IRP: Intramural Research Program HHS: U.S. Department of Health Biophysics Section, Molecular Targets and perspectives. Our findings also describe the and Human Services Medications Discovery Branch, National structural basis of allosteric mechanisms NCATS: National Center for Advancing Institute on Drug Abuse at these receptors. (Allosteric regulation is Translational Sciences Education: Beijing University, Beijing (B.S. NCBI: National Center for Biotechnology when a ligand, called an effector, binds to a Information in biochemistry and molecular biology); protein site that is topographically distinct NCCIH: National Center for Complementary and Integrative Health Columbia University Medical Center, from a protein’s active site in which the New York (M.A., M.Phil., and Ph.D. in NCI: National Cancer Institute activity characterizing the protein is carried NEI: National Eye Institute pharmacology) out.) These mechanistic findings are being NHGRI: National Human Genome Research Institute Training: Postdoctoral training in molecular leveraged to identify novel lead compounds recognition at Columbia University College NHLBI: National Heart, Lung, for both research and therapeutic purposes. and Blood Institute of Physicians and Surgeons (New York) and For neurotransmitter transporters, we NIA: National Institute on Aging in physiology, biophysics, and computational NIAAA: National Institute on Alcohol defined a novel allosteric mechanism of Abuse and Alcoholism biomedicine at Weill Medical College of transport. Based on these findings, we and NIAID: National Institute of Allergy Cornell University (New York) our collaborators discovered and optimized and Infectious Diseases Before coming to NIH: Assistant professor, NIAMS: National Institute of Arthritis high-affinity allosteric inhibitors bound and Musculoskeletal and Skin Diseases Department of Physiology and Biophysics, to serotonin transporters. Thus we have NIBIB: National Institute of Biomedical Weill Medical College of Cornell University Imaging and Bioengineering opened the door for clinical translation of NICHD: Eunice Kennedy Shriver Came to NIH: In 2015 allosteric inhibitors to reduce the side effects National Institute of Child Health and Human Development Outside interests: Playing and watching of current antidepressants. sports; enjoying wine; watching movies NIDA: National Institute on Drug Abuse NIDCD: National Institute on Deafness Website: https://irp.nih.gov/pi/lei-shi and Other Communication Disorders NIDCR: National Institute of Dental and Craniofacial Research Research interests: Membrane proteins NIDDK: National Institute of Diabetes (MP) initiate intracellular signaling and Digestive and Kidney Diseases NIEHS: National Institute of pathways, control the flow of energy and Environmental Health Sciences materials in and out of the cell, and thereby NIGMS: National Institute of General Medical Sciences account for more than 30% of the human NIMH: National Institute of Mental Health proteome and 40% of drug targets. My NIMHD: National Institute on Minority lab is investigating the structural basis of Health and Health Disparities NINDS: National Institute of MP functions to advance the mechanistic Neurological Disorders and Stroke understanding of key cellular processes. NINR: National Institute of Nursing Research Using a combined computational and NLM: National Library of Medicine OD: Office of the Director experimental approach, we identify and OITE: Office of Intramural Training characterize the elements that determine and Education the recognitions between MPs and their OIR: Office of Intramural Research ORS: Office of Research Services corresponding ligands, between MPs and ORWH: Office of Research on Women’s Health their coupled proteins, and between MPs OTT: Office of Technology Transfer

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