multiple sclerosis
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
Childhood Cancer: Novel Nanoparticle Shows Early Promise for Brain Tumor
Posted on by Lawrence Tabak, D.D.S., Ph.D.
The human brain is profoundly complex, consisting of tens of billions of neurons that form trillions of interconnections. This complex neural wiring that allows us to think, feel, move, and act is surrounded by what’s called the blood-brain barrier (BBB), a dense sheet of cells and blood vessels. The BBB blocks dangerous toxins and infectious agents from entering the brain, while allowing nutrients and other essential small molecules to pass right through.
This gatekeeping function helps to keep the brain healthy, but not when the barrier prevents potentially life-saving drugs from reaching aggressive, inoperable brain tumors. Now, an NIH-funded team reporting in the journal Nature Materials describes a promising new way to ferry cancer drugs across the BBB and reach the sites of disease [1]. While the researchers have not yet tried this new approach in people, they have some encouraging evidence from studies in mouse models of medulloblastoma, an aggressive brain cancer that’s diagnosed in hundreds of children each year.
The team, including Daniel Heller, Memorial Sloan Kettering Cancer Center, New York, NY, and Praveen Raju, Icahn School of Medicine at Mount Sinai, New York, NY, wanted to target a protein called P-selectin. The protein is found on blood vessel cells at sites of infection, injury, or inflammation, including cancers. The immune system uses such proteins to direct immune cells to the places where they are needed, allowing them to exit the bloodstream and enter other tissues.
Heller’s team thought they could take advantage of P-selectin and its molecular homing properties as a potential way to deliver cancer drugs to patients. But first they needed to package the drugs in particles tiny enough to stick to P-selectin like an immune cell.
That’s when they turned to a drug-delivery construct called a nanoparticle, which can have diameters a thousand times smaller than that of a human hair. But what’s pretty unique here is the nanoparticles are made from chains of sugar molecules called fucoidan, which are readily extracted from a type of brown seaweed that grows in Japan. It turns out that this unlikely ingredient has a special ability to attract P-selectin.
In the new study, the researchers decided to put their novel fucoidan nanoparticles to the test in the brain, while building on their previous animal work in the lungs [2]. That work showed that when fucoidan nanoparticles bind to P-selectin, they trigger a process that shuttles them across blood vessel walls.
This natural mechanism should also allow nanoparticle-packaged substances in the bloodstream to pass through vessel walls in the BBB and into the surrounding brain tissue. The hope was it would do so without damaging the BBB, a critical step for improving the treatment of brain tumors.
In studies with mouse models of medulloblastoma, the team loaded the nanoparticles with a cancer drug called vismodegib. This drug is approved for certain skin cancers and has been tested for medulloblastoma. The trouble is that the drug on its own comes with significant side effects in children at doses needed to effectively treat this brain cancer.
The researchers found that the vismodegib-loaded nanoparticles circulating in the mice could indeed pass through the intact BBB and into the brain. They further found that the particles accumulated at the site of the medulloblastoma tumors, where P-selectin was most abundant, and not in other healthy parts of the brain. In the mice, the approach allowed the vismodegib treatment to work better against the cancer and at lower doses with fewer side effects.
This raised another possibility. Radiation is a standard therapy for children and adults with brain tumors. The researcher found that radiation boosts P-selectin levels specifically in tumors. The finding suggests that radiation targeting specific parts of the brain prior to nanoparticle treatment could make it even more effective. It also may help to further limit the amount of cancer-fighting drug that reaches healthy brain cells and other parts of the body.
The fucoidan nanoparticles could, in theory, deliver many different drugs to the brain. The researchers note their promise for treating brain tumors of all types, including those that spread to the brain from other parts of the body. While much more work is needed, these seaweed-based nanoparticles may also help in delivering drugs to a wide range of other brain conditions, such as multiple sclerosis, stroke, and focal epilepsy, in which seizures arise from a specific part of the brain. It’s a discovery that brings new meaning to the familiar adage that good things come in small packages.
References:
[1] P-selectin-targeted nanocarriers induce active crossing of the blood-brain barrier via caveolin-1-dependent transcytosis. Tylawsky DE, Kiguchi H, Vaynshteyn J, Gerwin J, Shah J, Islam T, Boyer JA, Boué DR, Snuderl M, Greenblatt MB, Shamay Y, Raju GP, Heller DA. Nat Mater. 2023 Mar;22(3):391-399.
[2] P-selectin is a nanotherapeutic delivery target in the tumor microenvironment. Shamay Y, Elkabets M, Li H, Shah J, Brook S, Wang F, Adler K, Baut E, Scaltriti M, Jena PV, Gardner EE, Poirier JT, Rudin CM, Baselga J, Haimovitz-Friedman A, Heller DA. Sci Transl Med. 2016 Jun 29;8(345):345ra87.
Links:
Medulloblastoma Diagnosis and Treatment (National Cancer Institute/NIH)
Brain Basics: Know Your Brain (National Institute of Neurological Disorders and Stroke/NIH)
The Daniel Heller Lab (Memorial Sloan Kettering Cancer Center, New York, NY)
Praveen Raju (Mount Sinai, New York, NY)
NIH Support: National Cancer Institute; National Institute of Neurological Disorders and Stroke
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)
New Imaging Approach Reveals Lymph System in Brain
Posted on by Dr. Francis Collins
Considering all the recent advances in mapping the complex circuitry of the human brain, you’d think we’d know all there is to know about the brain’s basic anatomy. That’s what makes the finding that I’m about to share with you so remarkable. Contrary to what I learned in medical school, the body’s lymphatic system extends to the brain—a discovery that could revolutionize our understanding of many brain disorders, from Alzheimer’s disease to multiple sclerosis (MS).
Researchers from the National Institute of Neurological Disorders and Stroke (NINDS), the National Cancer Institute (NCI), and the University of Virginia, Charlottesville made this discovery by using a special MRI technique to scan the brains of healthy human volunteers [1]. As you see in this 3D video created from scans of a 47-year-old woman, the brain—just like the neck, chest, limbs, and other parts of the body—possesses a network of lymphatic vessels (green) that serves as a highway to circulate key immune cells and return metabolic waste products to the bloodstream.
