Joel Dudley, PhD, right, and Sam Gandy, MD, PhD, led a study that used an entirely data-driven approach to examine the impact of viruses on Alzheimer’s disease.
Two strains of human herpesvirus—human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7)—are found in the brains of individuals with Alzheimer’s disease at levels up to twice as high as in those without Alzheimer’s, according to findings published June 21, 2018, in Neuron by a team of Icahn School of Medicine at Mount Sinai researchers.
These common viruses, best known for causing roseola, a skin rash in children, can also be present in the brain and remain inactive for years. They also can cause encephalitis and other chronic disorders.
It is the first study to use an entirely data-driven approach to examine the impact of viruses on Alzheimer’s—and to identify potential disease-associated roles of these particular viruses, which was an unexpected discovery.
The researchers had been comparing genetic data in healthy and postmortem Alzheimer’s brains to identify possible new drug targets for Alzheimer’s disease when their complex computations revealed the unusually high levels of the viral genomes.
“This study represents a significant leap forward in our understanding of how viruses may play a role in Alzheimer’s disease,” says the study’s senior author, Joel Dudley, PhD, Mount Sinai Professor in Biomedical Data Science, and the Director of the Icahn School of Medicine’s Institute for Next Generation Healthcare. “We were able to not only measure these viruses using computational techniques but also build out the networks in which these viruses are operating and influencing known Alzheimer’s genes.”
The study was enabled in part by powerful new molecular profiling data released by the National Institute on Aging (NIA) Accelerating Medicines Partnership-Alzheimer’s Disease, a collaboration among industry, government, and nonprofit organizations dedicated to identifying new targets for preventing or treating the disease. Using those data, the team conducted computer mapping of four brain regions from more than 600 samples from the Mount Sinai Brain Bank, which for the last 36 years has been examining postmortem brain tissue from donors for Alzheimer’s-related research.
As the study progressed, the team found the higher levels of HHV6A and HHV7 viruses, which was subsequently confirmed using data from brain banks in three other major NIA Alzheimer’s Centers. Researchers also discovered that the viruses appeared to accelerate the development of Alzheimer’s-related plaques and tangles in the brain.
“Our team was initially quite skeptical about these findings,” says the study co-senior author, Sam Gandy, MD, PhD, Mount Sinai Professor in Alzheimer’s Research and the Director of the Center for Cognitive Health and NFL Neurological Care at Mount Sinai. “Gradually, we became convinced that what we were seeing is a real property of Alzheimer’s brains in several internationally recognized brain banks, and that we ought to report it, even if we cannot completely explain what these viruses are doing in the brain.”
Although the study does not prove a direct causal role between these herpesviruses and Alzheimer’s disease, or indicate what activates the viruses, the findings do lend credence to the hypothesis that these herpesviruses may trigger progression of dementia in Alzheimer’s. This work also opens new avenues for the identification of subpopulations and biomarkers, which would not only make it easier to diagnose and determine a person’s risk of developing Alzheimer’s but also possibly create opportunities to use existing antiviral drugs and drugs that stop the brain’s immune cells from responding to these viruses.
“We have been inundated with letters and emails from people sharing stories about viral infection and Alzheimer’s disease in their personal or family life, and that is an impetus for us to find an effective therapy as soon as we can,” Dr. Dudley says.
The Mount Sinai team that used an experimental treatment was led by interventional neuroradiologist Alejandro Berenstein, MD, and included Michelle Sorscher, RN, MSN, Clinical Program Manager, Neurosurgery.
When, in early 2017, the teacher of 14-year-old Shawn Svoboda called to say he was falling asleep in class, his mother wasn’t overly concerned, considering it typical teenage behavior.
However, when the teacher called a second time that same day to emphasize she thought this was something out of the ordinary, his mom requested that their pediatrician order a sleep study, as she had noticed subtle changes in Shawn, such as snoring, pulsating neck veins, muffled voice, clumsiness, and headaches, all of which she had chalked up to changes of puberty.
The results showed Shawn was suffering from central sleep apnea at the rate of 150 episodes per hour, and a brain MRI was immediately scheduled at their local hospital in Springfield, Massachusetts. The MRI showed an extensive, potentially lethal, arteriovenous (AV) fistula—an abnormal connection between an artery and a vein—at multiple sites in the brain, creating a complex tangle of blood vessels in the dura, or outer covering of the brain. Shawn was then referred for a genetics consult and a cardiology workup and met with a pediatric neurosurgeon in Connecticut.
After performing a brain angiogram, the neurosurgeon told Shawn’s parents that the condition was more extensive than originally believed and recommended that they take him to The Mount Sinai Hospital, to be seen by Alejandro Berenstein, MD, Professor of Neurosurgery, Radiology, and Pediatrics, at the Icahn School of Medicine at Mount Sinai, and Director of the Pediatric Cerebrovascular Program. Dr. Berenstein is a world-renowned interventional neuroradiologist who has vastly expanded the understanding and treatment of vascular abnormalities in the brain, pioneering the use of innovative substances to incrementally block off these abnormal blood vessels.
Without treatment, Dr. Berenstein says that Shawn was at risk for developing more neurological deficits, seizures, hemorrhage, or stroke. “He was a walking time bomb,” says his mom, Bonnie Kmon, RN, and an oncology certified nurse.
Typically, Dr. Berenstein would treat an AV fistula by injecting a standard medical-grade super glue—a lava-like embolism agent—through a catheter to seal the blood vessel, guided by real-time X-ray imaging.
Shawn’s situation was more complex: the extensive quantity needed would appear black in the X-ray, making it impossible for the surgical team to see what they were doing.
Dr. Berenstein was familiar with a different, liquid embolic super-glue substance being used outside of the United States called PHIL™ (Precipitating Hydrophobic Injectable Liquid), which is less dense and, using iodine, appears grey, instead of black, on an X-ray, making it possible to clearly see the areas being treated.
However, PHIL has not yet been approved by the U.S. Food and Drug Administration (FDA), so Dr. Berenstein and his team successfully petitioned the FDA to grant approval for a single patient compassionate use of PHIL, making Mount Sinai the first institution in the nation to use this agent. Dr. Berenstein was able to block off the abnormal blood vessels a few at a time.
The procedure had to be done in stages to allow the brain and heart to adjust to new blood-flow patterns. It took seven eight-hour procedures, over the course of more than a year, to complete treatment, and Shawn’s road to recovery was not an easy one. He developed blood clots in his brain on two separate occasions, had one grand mal seizure, and now needs to receive twice-daily injections of a blood thinner.
Amazingly, he has suffered no significant neurological deficits, his sleep apnea has completely resolved, he has better balance, is performing wonderfully in school, and no longer suffers from headaches. His genetics workup also showed that he suffers from PTEN Hamartoma Tumor Syndrome, which will require him to have continual yearly monitoring for other medical problems.
“Shawn’s recovery has been extraordinary,” says Dr. Berenstein. “Time will tell, but I expect this to be a permanent fix and I think he’ll continue to do very well.”
Shawn’s mom echoed his assessment, and is grateful, she says, to Dr. Berenstein and his “phenomenal” team of doctors and nurses who cared for Shawn throughout his journey.
Dr. Alejandro Berenstein receives financial compensation as a consultant for MicroVention, the manufacturer of the Precipitating Hydrophobic Injectable Liquid System (PHIL).
Study investigators Adolfo García-Sastre, PhD, left, and Guojun Wang, PhD, Postdoctoral Fellow
Dogs are becoming increasingly friendly hosts for a surprising array of influenza viruses, a situation that could pose a potential threat to humans. That is the finding of a new study from the Global Health and Emerging Pathogens Institute at the Icahn School of Medicine at Mount Sinai, published June 5, 2018, in mBio.
The results were based on scientific evidence that dogs in southern China had the capacity to serve as “mixing vessels” for influenza viruses they receive from swine and birds—two animals considered to be the most common reservoirs of influenza viral genetic diversity.
“The more diversity we see in influenza viruses, the greater the chance they could jump from one host to another,” says the study’s lead author, Adolfo García-Sastre, PhD, Professor of Microbiology at the Icahn School of Medicine, and Director of the Global Health and Emerging Pathogens Institute. He is also Director of the Center for Research on Influenza Pathogenesis, one of five National Institutes of Health (NIH) Centers of Excellence for Influenza Research and Surveillance. The research took place in the Guangxi region of southern China, an area where diverse animal species are raised in proximity to one another and intermingle in live-animal markets.
In the study, researchers swabbed the noses of some 800 dogs that had all been brought to veterinarians or clinics in the region after showing respiratory symptoms consistent with canine influenza. The scientists sequenced the complete genomes of 16 influenza A viruses obtained from the dogs. All of these strains represented introductions of H1N1 swine influenza viruses circulating in pigs in Asia and Europe into these dogs.
They also found a set of three new viruses (H1N1r, H1N2r, and H3N2r) in which these swine-origin canine influenza viruses exchanged genes with previously identified avian-origin H3N2 canine influenza viruses.
Flu viruses have eight mini chromosomes and when two different strains infect the same cell they can exchange genetic segments, a process known as reassortment. All pandemic flu viruses that have been tracked have involved reassortment. The 2009 H1N1 swine-origin human influenza pandemic, for example, was a derivative of two different strains of swine influenza, one that had been circulating in Asia and Europe and the other in the Americas, particularly North America. That pandemic virus traced to a very small region in central Mexico, and was responsible for more than 17,000 deaths worldwide when it jumped from pigs into humans.
There is no known case of a human contracting a canine flu. Nor is it certain that the new strains of dog flu virus discovered in China would have that transmission capability. Still, as Dr. García-Sastre points out, the potential exists, especially in light of the frequent contact between pets and their owners. Moreover, the health risk increases for humans who have not previously been exposed to these viral strains and have not built an immunity to them.
Dr. García-Sastre does not predict a new pandemic, but he says there is a need for additional research and heightened vigilance by public health authorities around the world.
“We must start thinking about dogs as potential reservoirs for influenza viruses,” he says. “The more awareness we create, the more likely that countermeasures can be developed by countries to diminish the circulation of influenza virus in domestic animals.”
Dr. Holland’s children, from left: David Holland; Diane Holland; Sally Holland; Peter Holland; Mary Holland; and Steven Holland, MD.
Family, friends, and colleagues of the late James F. Holland, MD, Distinguished Professor of Neoplastic Diseases at The Tisch Cancer Institute, gathered in May at the Mount Sinai Health System to celebrate his work as a renowned physician-scientist who helped cure acute lymphoblastic leukemia in children.
Dr. Holland’s work helped establish oncology as a medical discipline. In the 1950s, when chemotherapy was a relatively new treatment, he and his colleagues began treating seemingly incurable patients with drug combinations rather than administering each one sequentially. Nine out of 10 patients successfully responded to the therapy. Combination chemotherapy remains the standard of care today. Dr. Holland encouraged physicians to share data and create common protocols. In 1972, he received the prestigious Albert Lasker Clinical Medical Research Award.
James F. Holland, MD
Speakers at Mount Sinai’s Celebration of Life event included many esteemed physicians from around the country whom Dr. Holland influenced and once mentored, as well as Mount Sinai leaders in academic affairs and cancer research. Dr. Holland’s six adult children attended the event, with several sharing their thoughts and memories.
In his opening remarks, William K. Oh, MD, Deputy Director of The Tisch Cancer Institute and Chief of Hematology and Medical Oncology, said Dr. Holland “was absolutely committed to changing the poor outcomes of patients with leukemia, breast cancer, and other devastating cancers by investing in translational research and clinical trials, principles that drive our work at The Tisch Cancer Institute today.”
Panelists included, from left: Anthony Fargnoli, PhD, Assistant Professor, Medicine (Cardiology); Jonathan A. Cohen, DVM, Director, Center for Comparative Medicine and Surgery; Paula Croxson, PhD, Assistant Professor, Neuroscience, and Psychiatry; Yasmin Hurd, PhD; Stacey Baker, PhD, Assistant Professor, Oncological Sciences; and Randy Albrecht, PhD, Associate Professor, Microbiology. Not pictured, Giorgio Martinelli, PhD, Associate Professor, Neurology.
Seven researchers and veterinarians from the Mount Sinai Health System discussed humane animal research at a panel held at Hatch Auditorium to commemorate Biomedical Research Awareness Day (BRAD) on Thursday, April 19. They joined more than 110 other international institutions in acknowledging the important role that laboratory animals play in advancing new treatments for complex conditions that include, but are not limited to, Alzheimer’s disease, cancer, and addiction.
“Animal models that mimic the human condition can help us focus on one chemical in an effort to start to figure out new treatments,” said Yasmin Hurd, PhD, Director of the Addiction Institute at Mount Sinai, who works with rodents to study the developmental effects of cannabis. Through these studies, Dr. Hurd has found that cannabidiol—a chemical found in marijuana—can be used in humans to decrease opioid-seeking behavior.
“For a very long time, the scientific community has been quiet about animal research,” said Jaclyn R. Steinbach, BVetMed (Hons), MRCVS, Clinical Veterinarian and Instructor, Center for Comparative Medicine and Surgery, who was the organizer of the event. “We need to share what we are doing and show that we are proud.”
Barbara Murphy, MD, Chair of the Samuel Bronfman Department of Medicine at the Icahn School of Medicine at Mount Sinai, was a featured speaker at the May 2018 graduation ceremony of her alma mater, the School of Medicine of the Royal College of Surgeons in Ireland (RCSI).
During the event, Dr. Murphy—a pioneering nephrologist and immunology researcher, the Murray M. Rosenberg Professor of Medicine, and Dean for Clinical Integration and Population Health, at the Icahn School of Medicine—received a prestigious Honorary Doctorate Degree from RCSI, an award she found particularly gratifying. RCSI is based in Dublin, her hometown. Dr. Murphy was one of three siblings who graduated from RCSI with a medical degree, and her parents were again in the audience cheering her on.
“It was a chance to look back and see what pieces of advice I would have given myself as a graduate 29 years ago,” she said. Her advice was straightforward. “Do not be afraid to stand up and take risks for the good of your patients,” Dr. Murphy told the 283 graduates, who came from 29 countries. “You cannot have an impact if you live in the shadows afraid to fail or afraid of upsetting others. Success is not about abstracts, papers, awards, or titles. It is about having a positive impact on the lives of others, about meaningful change.”
Dr. Murphy discussed a highlight of her career, her work as a young physician at Mount Sinai in 1997, where she helped establish the feasibility of performing kidney transplants on patients with HIV, which is the standard of care today.
“We were still in the midst of the AIDS crisis, patients had staggering mortality rates and were socially ostracized,” she said. “I had met precisely two people affected by HIV prior to arriving in New York, and was now faced with many otherwise ‘healthy’ HIV patients who had no hope of getting off dialysis.” She and a small group of other researchers from eight U.S. medical centers—with support from the National Institutes of Health—found a clear scientific rationale for moving forward with transplants.
“We faced resistance,” she said, “and were even verbally abused and insulted by people who did not look at patient suffering, the science, or the data, but rather felt it was their right to pass moral judgment on people with HIV, and that there was a moral hierarchy when it came to allocation of donor kidneys.” Interestingly, she added, “Two weeks ago we received an email from one of our patients who was in that trial thanking us on his 15th renal transplant birthday!”
During medical school, Dr. Murphy said she planned on becoming a full-time clinician, not a researcher, and that the field of genomics research did not exist. “You cannot predict the circumstances, opportunities, discoveries that will occur that will change your lives,” she told the audience. “The question is, will you step forward and run with it when opportunity comes your way, or will you choose the status quo?”
Recently, Dr. Murphy took on an additional leadership role as Chair of the Scientific Advisory Board of RenalytixAI, Plc. RenalytixAI has partnered with the Mount Sinai Health System to create a novel artificial intelligence-based platform, KidneyTrack™, that predicts a patient’s risk for progressive chronic kidney disease.
