virus
Study Reveals How Epstein-Barr Virus May Lead to Cancer
Posted on by Lawrence Tabak, D.D.S., Ph.D.
Chances are good that you’ve had an Epstein-Barr virus (EBV) infection, usually during childhood. More than 90 percent of us have, though we often don’t know it. That’s because most EBV infections are mild or produce no symptoms at all.
But in some people, EBV can lead to other health problems. The virus can cause infectious mononucleosis (“mono”), type 1 diabetes, and other ailments. It also can persist in our bodies for years and cause increased risk later in life for certain cancers, such as lymphoma, leukemia, and head and neck cancer. Now, an NIH-funded team has some of the best evidence yet to explain how this EBV that hangs around may lead to cancer [1].
The paper, published recently in the journal Nature, shows that a key viral protein readily binds to a particular spot on a particular human chromosome. Where the protein accumulates, the chromosome becomes more prone to breaking for reasons that aren’t yet fully known. What the study makes clearer is that the breakage produces latently infected cells that are more likely over time to become cancerous.
This discovery paves the way potentially for ways to screen for and identify those at particular risk for developing EBV-associated cancers. It may also fuel the development of promising new ways to prevent these cancers from arising in the first place.
The work comes from a team led by Don Cleveland and Julia Su Zhou Li, University of California San Diego’s Ludwig Cancer Research, La Jolla, CA. Over the years, it’s been established that EBV, a type of herpes virus, often is detected in certain cancers, particularly in people with a long-term latent infection. What interested the team is a viral protein, called EBNA1, which routinely turns up in those same EBV-related cancers.
The EBNA1 protein is especially interesting because it binds viral DNA in particular spots, which allows the virus to persist and make more copies of itself. This discovery raised the intriguing possibility that the protein may also bind similar sequences in human DNA. While it had been suggested previously that this interaction might play a role in EBV-associated cancers, the details had remained murky—until now.
In the new study, the researchers first made uninfected human cells produce the viral EBNA1 protein. They then peered inside them with a microscope to see where those proteins went. In both healthy and cancerous human cells, they watched as EBNA1 proteins built up at two distinct spots and confirmed that this accumulation was dependent on the protein’s ability to bind DNA.
Next, they mapped where exactly EBNA1 binds to human DNA. Interestingly, it was along a repetitive non-protein-coding stretch of DNA on human chromosome 11. This region includes more than 300 copies of an 18-letter sequence that looks quite similar to the EBNA1-binding sites in its own viral genome.
What’s more, the researchers noticed that the repetitive DNA there takes on a structure that’s known for being unstable. And these so-called fragile sites are inherently prone to breaking.
The team went on to uncover evidence that the buildup of EBNA1 at this already fragile site only makes matters worse. In EBV-infected cells, increasing the amount of EBNA1 protein led to more chromosome 11 breaks. Those breaks showed up within a single day in about 40 percent of cells.
For these cells, those breaks also may be a double whammy. That’s because the breaks are located next to neighboring genes with long recognized roles in regulating cell growth. When altered, these genes can contribute to turning a cell cancerous.
To further nail down the link to cancer, the researchers looked to whole-genome sequencing data for more than 2,400 cancers including 38 tumor types from the international Pan-Cancer Analysis of Whole Genomes consortium [2]. They found that tumors with detectable EBV also had an unusually high number of chromosome 11 abnormalities. In fact, that was true in every single case of head and neck cancer.
The findings suggest that people will vary in their susceptibility to EBNA1-induced DNA breaks along chromosome 11 based on the amount of EBNA1 protein in their latently infected cells. It also will depend on the number of EBV-like DNA repeats present in their DNA.
Given these new findings, it’s worth noting that the presence of EBV and the very same viral protein has been implicated also in the link between EBV and multiple sclerosis (MS) [3]. Together, these recent findings are a reminder of the value in pursuing an EBV vaccine that might thwart this infection and its associated conditions, including certain cancers and MS. And, we’re getting there. In fact, an early-stage clinical trial for an experimental EBV vaccine is now ongoing here at the NIH Clinical Center.
References:
[1] Chromosomal fragile site breakage by EBV-encoded EBNA1 at clustered repeats. Li JSZ, Abbasi A, Kim DH, Lippman SM, Alexandrov LB, Cleveland DW. Nature. 2023 Apr 12.
[2] Pan-cancer analysis of whole genomes. ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Nature.2020 Feb;578(7793):82-93.
[3] Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Lanz TV, Brewer RC, Steinman L, Robinson WH, et al. Nature. 2022 Mar;603(7900):321-327.
Links:
About Epstein-Barr Virus (Centers for Disease Control and Prevention, Atlanta)
Head and Neck Cancer (National Cancer Institute,/NIH)
Multiple Sclerosis (National Institute of Neurological Disorders and Stroke/NIH)
Don W. Cleveland Lab (University of California San Diego, La Jolla, CA)
NIH Support: National Institute of General Medical Sciences; National Institute of Environmental Health Sciences; National Cancer Institute
A Look Back at Science’s 2022 Breakthroughs
Posted on by Lawrence Tabak, D.D.S., Ph.D.
Happy New Year! I hope everyone finished 2022 with plenty to celebrate, whether it was completing a degree or certification, earning a promotion, attaining a physical fitness goal, or publishing a hard-fought scientific discovery.
If the latter, you are in good company. Last year produced some dazzling discoveries, and the news and editorial staff at the journal Science kept a watchful eye on the most high-impact advances of 2022. In December, the journal released its list of the top 10 advances across the sciences, from astronomy to zoology. In case you missed it, Science selected NASA’s James Webb Space Telescope (JWST) as the 2022 Breakthrough of the Year [1].
This unique space telescope took 20 years to complete, but it has turned out to be time well spent. Positioned 1.5-million-kilometers from Earth, the JWST and its unprecedented high-resolution images of space have unveiled the universe anew for astronomers and wowed millions across the globe checking in online. The telescope’s image stream, beyond its sheer beauty, will advance study of the early Universe, allowing astronomers to discover distant galaxies, explore the early formation of stars, and investigate the possibility of life on other planets.
While the biomedical sciences didn’t take home the top prize, they were well represented among Science’s runner-up breakthroughs. Some of these biomedical top contenders also have benefited, directly or indirectly, from NIH efforts and support. Let’s take a look:
RSV vaccines nearing the finish line: It’s been one of those challenging research marathons. But scientists last year started down the homestretch with the first safe-and-effective vaccine for respiratory syncytial virus (RSV), a leading cause of severe respiratory illness in the very young and the old.
In August, the company Pfizer presented evidence that its experimental RSV vaccine candidate offered protection for those age 60 and up. Later, they showed that the same vaccine, when administered to pregnant women, helped to protect their infants against RSV for six months after birth. Meanwhile, in October, the company GSK announced encouraging results from its late-stage phase III trial of an RSV vaccine in older adults.
As Science noted, the latest clinical progress also shows the power of basic science. For example, researchers have been working with chemically inactivated versions of the virus to develop the vaccine. But these versions have a key viral surface protein that changes its shape after fusing with a cell to start an infection. In this configuration, the protein elicits only weak levels of needed protective antibodies.
Back in 2013, Barney Graham, then with NIH’s National Institute of Allergy and Infectious Diseases (NIAID), and colleagues, solved the problem [2]. Graham’s NIH team discovered a way to lock the protein into its original prefusion state, which the immune system can better detect. This triggers higher levels of potent antibodies, and the discovery kept the science—and the marathon—moving forward.
These latest clinical advances come as RSV and other respiratory viruses, including SARS-CoV-2, the cause of COVID-19, are sending an alarming number of young children to the hospital. The hope is that researchers will cross the finish line this year or next, and we’ll have the first approved RSV vaccine.
Virus fingered as cause of multiple sclerosis: Researchers have long thought that multiple sclerosis, or MS, has a viral cause. Pointing to the right virus with the required high degree of certainty has been the challenge, slowing progress on the treatment front for those in need. As published in Science last January, Alberto Ascherio, Harvard T.H. Chan School of Public Health, Boston, and colleagues produced the strongest evidence yet that MS is caused by the Epstein-Barr virus (EBV), a herpesvirus also known for causing infectious mononucleosis [3].
The link between EBV and MS had long been suspected. But it was difficult to confirm because EBV infections are so widespread, and MS is so disproportionately rare. In the recent study, the NIH-supported researchers collected blood samples every other year from more than 10 million young adults in the U.S. military, including nearly 1,000 who were diagnosed with MS during their service. The evidence showed that the risk of an MS diagnosis increased 32-fold after EBV infection, but it held steady following infection with any other virus. Levels in blood serum of a biomarker for MS neurodegeneration also went up only after an EBV infection, suggesting that the viral illness is a leading cause for MS.
Further evidence came last year from a discovery published in the journal Nature by William Robinson, Stanford University School of Medicine, Stanford, CA, and colleagues. The NIH-supported team found a close resemblance between an EBV protein and one made in the healthy brain and spinal cord [4]. The findings suggest an EBV infection may produce antibodies that mistakenly attack the protective sheath surrounding our nerve cells. Indeed, the study showed that up to one in four people with MS had antibodies that bind both proteins.
This groundbreaking research suggests that an EBV vaccine and/or antiviral drugs that thwart this infection might ultimately prevent or perhaps even cure MS. Of note, NIAID launched last May an early-stage clinical trial for an experimental EBV vaccine at the NIH Clinical Center, Bethesda, MD.
AI Gets Creative: Science’s 2021 Breakthrough of the Year was AI-powered predictions of protein structure. In 2022, AI returned to take another well-deserved bow. This time, Science singled out AI’s now rapidly accelerating entry into once uniquely human attributes, such as artistic expression and scientific discovery.
On the scientific discovery side, Science singled out AI’s continued progress in getting creative with the design of novel proteins for vaccines and myriad other uses. One technique, called “hallucination,” generates new proteins from scratch. Researchers input random amino acid sequences into the computer, and it randomly and continuously mutates them into sequences that other AI tools are confident will fold into stable proteins. This greatly simplifies the process of protein design and frees researchers to focus their efforts on creating a protein with a desired function.
AI research now engages scientists around world, including hundreds of NIH grantees. Taking a broader view of AI, NIH recently launched the Artificial Intelligence/Machine Learning Consortium to Advance Health Equity and Researcher Diversity (AIM-AHEAD) Program. It will help to create greater diversity within the field, which is a must. A lack of diversity could perpetuate harmful biases in how AI is used, how algorithms are developed and trained, and how findings are interpreted to avoid health disparities and inequities for underrepresented communities.
And there you have it, some of the 2022 breakthroughs from Science‘s news and editorial staff. Of course, the highlighted biomedical breakthroughs don’t capture the full picture of research progress. There were many other milestone papers published in 2022 that researchers worldwide will build upon in the months and years ahead to make further progress in their disciplines and, for some, draw the attention of Science’s news and editorial staff. Here’s to another productive year in biomedical research, which the blog will continue to feature and share with you as it unfolds in 2023.
References:
[1] 2022 Breakthrough of the Year. Science. Dec 15, 2022.
[2] Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody. McLellan JS, Chen M, Leung S, Kwong PD, Graham BS, et al. Science. 2013 May 31;340(6136):1113-1117.
[3] Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y, Elledge SJ, Niebuhr DW, Scher AI, Munger KL, Ascherio A. Science. 2022 Jan 21;375(6578):296-301.
[4] Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Lanz TV, Brewer RC, Steinman L, Robinson WH, et al. Nature. 2022 Mar;603(7900):321-327.
Links:
Respiratory Syncytial Virus (RSV) (National Institute of Allergy and Infectious Diseases/NIH)
Multiple Sclerosis (National Institute of Neurological Disorders and Stroke/NIH)
Barney Graham (Morehouse School of Medicine, Atlanta)
Alberto Ascherio (Harvard T.H. Chan School of Public Health, Boston)
Robinson Lab (Stanford Medicine, Stanford, CA)
James Webb Space Telescope (Goddard Space Flight Center/NASA, Greenbelt, MD)
Finding New Ways to Fight Coronavirus … From Studying Bats
Posted on by Dr. Francis Collins
David Veesler has spent nearly 20 years imaging in near-atomic detail the parts of various viruses, including coronaviruses, that enable them to infect Homo sapiens. In fact, his lab at the University of Washington, Seattle, was the first to elucidate the 3D architecture of the now infamous spike protein, which coronaviruses use to gain entry into human cells [1]. He uses these fundamental insights to guide the design of vaccines and therapeutics, including promising monoclonal antibodies.
Now, Veesler and his lab are turning to another mammal in their search for new leads for the next generation of antiviral treatments, including ones aimed at the coronavirus that causes COVID-19, SARS-CoV-2. With support from a 2020 NIH Director’s Pioneer Award, Veesler will study members of the order Chiroptera. Or, more colloquially, bats.
Why bats? Veesler says bats are remarkable creatures. They are the only mammals capable of sustained flight. They rarely get cancer and live unusually long lives for such small creatures. More importantly for Veesler’s research, bats host a wide range of viruses—more than any other mammal species. Despite carrying all of these viruses, bats rarely show symptoms of being sick. Yet they are the source for many of the viruses that have spilled over into humans with devastating effect, including rabies, Ebola virus, Nipah and Hendra viruses, severe acute respiratory syndrome coronavirus (SARS-CoV), and, likely, SARS-CoV-2.
Beyond what is already known about bats’ intriguing qualities, Veesler says humans still have much to discover about these flying mammals, including how their immune systems cope with such an onslaught of viral invaders. For example, it turns out that a bat’s learned, or adaptive, immune system is, for the most part, uncharted territory. As such, it offers an untapped source of potentially promising viral inhibitors just waiting to be unearthed, fully characterized, and then used to guide the development of new kinds of anti-viral therapeutics.
In his studies, Veesler will work with collaborators studying bats around the world to characterize their antibody production. He wants to learn how these antibodies contribute to bats’ impressive ability to tolerate viruses and other pathogens. What is it about the structure of bat antibodies that make them different from human antibodies? And, how can those structural differences serve as blueprints for promising new treatments to combat many potentially deadly viruses?
Interestingly, Veesler’s original grant proposal makes no mention of SARS-CoV-2 or COVID-19. That’s because he submitted it just months before the first reports of the novel coronavirus in Wuhan, China. But Veesler doesn’t consider himself a visionary by expanding his research to bats. He and others had been working on closely related coronaviruses for years, inspired by earlier outbreaks, including SARS in 2002 and Middle East respiratory syndrome (MERS) in 2012 (although MERS apparently came from camels). The researcher didn’t see SARS-CoV-2 coming, but he recognized the potential for some kind of novel coronavirus outbreak in the future.
These days, the Veesler lab has been hard at work to understand SARS-CoV-2 and the human immune response to the virus. His team showed that SARS-CoV-2 uses the human receptor ACE2 to gain entry into our cells [2]. He’s also a member of the international research team that identified a human antibody, called S309, from a person who’d been infected with SARS in 2003. This antibody is showing promise for treating COVID-19 [3], now in a phase 3 clinical trial in the United States.
In another recent study, reported as a pre-print in bioRxiv, Veesler’s team mapped dozens of distinct human antibodies capable of neutralizing SARS-CoV-2 by their ability to hit viral targets outside of the well-known spike protein [4]. Such discoveries may form the basis for new and promising combinations of antibodies to treat COVID-19 that won’t be disabled by concerning new variations in the SARS-CoV-2 spike protein. Perhaps, in the future, such therapeutic cocktails may include modified bat-inspired antibodies too.
References:
[1] Cryo-electron microscopy structure of a coronavirus spike glycoprotein trimer. Walls AC, Tortorici MA, Bosch BJ, Frenz B, Rottier PJM, DiMaio F, Rey FA, Veesler D. Nature. 2016 Mar 3;531(7592):114-117.
[2] Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Cell. 2020 Apr 16;181(2):281-292.e6.
[3] Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Pinto D, Park YJ, Beltramello M, Veesler D, Cortil D, et al. Nature.18 May 2020 [Epub ahead of print]
[4] N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2. McCallum M, Marco A, Lempp F, Tortorici MA, Pinto D, Walls AC, Whelan SPJ, Virgin HW, Corti D, Pizzuto MS, Veesler D, et al. bioRxiv. 2021 Jan 14.
Links:
COVID-19 Research (NIH)
Veesler Lab (University of Washington, Seattle)
Veesler Project Information (NIH RePORTER)
NIH Director’s Pioneer Award Program (Common Fund)
NIH Support: Common Fund; National Institute of Allergy and Infectious Diseases
Capturing Viral Shedding in Action
Posted on by Dr. Francis Collins
You’ve probably seen some amazing high-resolution images of SARS-CoV-2, the novel coronavirus that causes COVID-19, on television and the web. What you might not know is that many of these images, including the ones shown here, were produced at Rocky Mountain Laboratories (RML), a part of NIH’s National Institute of Allergy and Infectious Diseases (NIAID) that’s located in the small Montana town of Hamilton.
The head of RML’s Electron Microscopy Unit, Elizabeth Fischer, was the researcher who took this portrait of SARS-CoV-2. For more than 25 years, Fischer has snapped stunning images of dangerous viruses and microbes, including some remarkable shots of the deadly Ebola virus. She also took some of the first pictures of the coronavirus that causes Middle East respiratory syndrome (MERS), which arose from camels and continues to circulate at low levels in people.
The NIAID facility uses a variety of microscopy techniques, including state-of-the-art cryo-electron microscopy (cryo-EM). But the eye-catching image you see here was taken with a classic scanning electron microscope (SEM).
SEM enables visualization of particles, including viruses, that are too small to be seen with traditional light microscopy. It does so by focusing electrons, instead of light, into a beam that scans the surface of a sample that’s first been dehydrated, chemically preserved, and then coated with a thin layer of metal. As electrons bounce off the sample’s surface, microscopists such as Fischer are able to capture its precise topology. The result is a gray-scale micrograph like the one you see above on the left. To make the image easier to interpret, Fischer hands the originals off to RML’s Visual Medical Arts Department, which uses colorization to make key features pop like they do in the image on the right.
So, what exactly are you seeing in this image? The orange-brown folds and protrusions are part of the surface of a single cell that’s been infected with SARS-CoV-2. This particular cell comes from a commonly studied primate kidney epithelial cell line. The small, blue spheres emerging from the cell surface are SARS-CoV-2 particles.
This picture is quite literally a snapshot of viral shedding, a process in which viral particles are released from a dying cell. This image gives us a window into how devastatingly effective SARS-CoV-2 appears to be at co-opting a host’s cellular machinery: just one infected cell is capable of releasing thousands of new virus particles that can, in turn, be transmitted to others.
While capturing a fixed sample on the microscope is fairly straightforward for a pro like Fischer, developing a sample like this one involves plenty of behind-the-scenes trial and error by NIAID investigators. As you might imagine, to see the moment that viruses emerge from an infected cell, you have to get the timing just right.
By capturing many shots of the coronavirus using the arsenal of microscopes available at RML and elsewhere, researchers are learning more every day about how SARS-CoV-2 enters a cell, moves inside it, and then emerges to infect other cells. In addition to advancing scientific knowledge, Fischer notes that images like these also hold the remarkable power to make an invisible enemy visible to the world at large.
Making SARS-CoV-2 tangible helps to demystify the challenges that all of us now face as a result of the COVID-19 pandemic. The hope is it will encourage each and every one of us to do our part to fight it, whether that means digging into the research, working on the front lines, or staying at home to prevent transmission and flatten the curve. And, if you could use some additional inspiration, don’t miss the NIAID’s image gallery on Flickr, which includes some of Fischer’s finest work.
Links:
Coronavirus (COVID-19) (NIH)
Rocky Mountain Laboratories (National Institute of Allergy and Infectious Diseases/NIH)
Elizabeth Fischer (National Institute of Allergy and Infectious Diseases/NIH)
NIH Support: National Institute of Allergy and Infectious Diseases
Bringing Needed Structure to COVID-19 Drug Development
Posted on by Dr. Francis Collins
With so much information swirling around these days about the coronavirus disease 2019 (COVID-19) pandemic, it would be easy to miss one of the most interesting and significant basic science reports of the past few weeks. It’s a paper published in the journal Science [1] that presents an atomic-scale snapshot showing the 3D structure of the spike protein on the novel coronavirus attached to a human cell surface protein called ACE2, or angiotensin converting enzyme 2. ACE2 is the receptor that the virus uses to gain entry.
What makes this image such a big deal is that it shows—in exquisite detail—how the coronavirus attaches to human cells before infecting them and making people sick. The structural map of this interaction will help guide drug developers, atom by atom, in devising safe and effective ways to treat COVID-19.
This new work, conducted by a team led by Qiang Zhou, Westlake Institute for Advanced Study, Hangzhou, China, took advantage of a high-resolution imaging tool called cryo-electron microscopy (cryo-EM). This approach involves flash-freezing molecules in liquid nitrogen and bombarding them with electrons to capture their images with a special camera. When all goes well, cryo-EM can solve the structure of intricate macromolecular complexes in a matter of days, including this one showing the interaction between a viral protein and human protein.
Zhou’s team began by mapping the structure of human ACE2 in a complex with B0AT1, which is a membrane protein that it helps to fold. In the context of this complex, ACE2 is a dimer—a scientific term for a compound composed of two very similar units. Additional mapping revealed how the surface protein of the novel coronavirus interacts with ACE2, indicating how the virus’s two trimeric (3-unit) spike proteins might bind to an ACE2 dimer. After confirmation by further research, these maps may well provide a basis for the design and development of therapeutics that specifically target this critical interaction.
The ACE2 protein resides on the surface of cells in many parts of the human body, including the heart and lungs. The protein is known to play a prominent role in the body’s complex system of regulating blood pressure. In fact, a class of drugs that inhibit ACE and related proteins are frequently prescribed to help control high blood pressure, or hypertension. These ACE inhibitors lower blood pressure by causing blood vessels to relax.
Since the COVID-19 outbreak, many people have wondered whether taking ACE inhibitors would be helpful or detrimental against coronavirus infection. This is of particular concern to doctors whose patients are already taking the medications to control hypertension. Indeed, data from China and elsewhere indicate hypertension is one of several coexisting conditions that have consistently been reported to be more common among people with COVID-19 who develop life-threatening severe acute respiratory syndrome.
In a new report in this week’s New England Journal of Medicine, a team of U.K. and U.S. researchers, partly supported by NIH, examined the use of ACE inhibitors and other angiotensin-receptor blockers (ARBs) in people with COVID-19. The team, led by Scott D. Solomon of Brigham and Women’s Hospital and Harvard Medical School, Boston, found that current evidence in humans is insufficient to support or refute claims that ACE inhibitors or ARBs may be helpful or harmful to individuals with COVID-19.
The researchers concluded that these anti-hypertensive drugs should be continued in people who have or at-risk for COVID-19, stating: “Although additional data may further inform the treatment of high-risk patients … clinicians need to be cognizant of the unintended consequences of prematurely discontinuing proven therapies in response to hypothetical concerns.” [2]
Research is underway to generate needed data on the use of ACE inhibitors and similar drugs in the context of the COVID-19 pandemic, as well as to understand more about the basic mechanisms underlying this rapidly spreading viral disease. This kind of fundamental research isn’t necessarily the stuff that will make headlines, but it likely will prove vital to guiding the design of effective drugs that can help bring this serious global health crisis under control.
References:
[1] Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Science. 27 March 2020. [Epub ahead of publication]
[2] Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19. Vaduganathan M, Vardeny O, Michel T, McMurray J, Pfeffer MA, Solomon SD. 30 NEJM. March 2020 [Epub ahead of Publication]
Links:
Coronavirus (COVID-19) (NIH)
COVID-19, MERS & SARS (National Institute of Allergy and Infectious Diseases/NIH)
Transformative High Resolution Cryo-Electron Microscopy (Common Fund/NIH)
Qiang Zhou (Westlake Institute for Advanced Study, Zhejiang Province)
Scott D. Solomon (Brigham and Women’s Hospital, Boston)
NIH Support: National Center for Advancing Translational Sciences; National Heart, Lung, and Blood Institute
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