November 3, 2021
Recent NIH Research
The National Institutes of Health (NIH) is our nation’s medical research agency. Its mission focuses on scientific discoveries that improve health and save lives. Founded in 1870, the NIH conducts its own scientific research through its Intramural Research Program (IRP), which supports approximately 1,200 principal investigators and more than 4,000 postdoctoral fellows conducting basic, translational and clinical research. In this blog, we will highlight recent innovative NIH research.
IRP’s Steven Rosenberg receives HHS Secretary’s Award for Distinguished Service
Dr. Steven Rosenberg, Chief of Surgery at the National Cancer Institute, has been awarded the HHS Secretary’s Award for Distinguished Service in recognition of his groundbreaking research in cancer immunotherapy. He pioneered the development of immunotherapy, resulting in the first effective immunotherapy for selected patients with advanced stage cancer. Dr. Rosenberg is the first researcher to successfully insert foreign genes into humans, leading to the development of gene therapy as a novel technique in the treatment of disease. The award, which celebrates excellence in leadership, ability, and service, is the highest honor given by the US Department of Health and Human Services.
Throughout his 47 year career at NCI, Dr. Rosenberg has been at the forefront of using immunotherapy and gene therapy to treat multiple forms of cancer, including kidney cancer, lymphoma, and melanoma. This innovative treatment directly targets tumors without the destruction of healthy tissue that occurs with traditional methods such as surgery, chemotherapy and radiation treatment. “One of the major advantages of immunotherapy is it can be highly specific in its recognition of affected cells,” Dr. Rosenberg explains. The therapies based upon his work have even proven capable of combating ‘metastatic’ cancers that have spread around the body from the site where they first developed.
As a young surgical resident at what is now Brigham and Women’s Hospital in Boston, Dr. Rosenberg was assigned to work at the VA Hospital in West Roxbury. There, he encountered a patient who needed his gallbladder removed, but a quick review of the patient’s medical records showed something very unusual. Twelve years earlier, the patient had undergone surgery to remove a stomach tumor. The notes indicated that several tumors couldn’t be removed, and the patient had received no further treatment. Yet when Dr. Rosenberg performed the gallbladder surgery, there was no sign of the old cancer.
“It’s one of the rarest events in medicine,” Dr. Rosenberg says. “Somehow his body had learned to defeat the disease, and it seemed likely to me that the immune system was responsible.”
In another case that occurred during his residency, Dr. Rosenberg saw a patient that had received a donated kidney that his doctors later learned contained cancerous cells. With the patient’s immune system disabled so his body would not reject the new kidney, the cancer quickly spread. When his doctors discontinued the immunosuppressive drug regimen, the patient’s body rejected the kidney, as expected, but surprisingly also started attacking the cancer, including the cancer cells that had spread from the donated organ. “That demonstrated to me that if you have a strong enough immune stimulus, the body was capable of rejecting even large, invasive cancers,” Dr. Rosenberg explains.
After joining the NIH in 1974, Dr. Rosenberg focused his work on studying immune cells called lymphocytes, which are white blood cells that fight infection. His research team determined they could remove lymphocytes that had infiltrated the tumor and were already fighting the cancer and treat the extracted cells in in the lab with a hormone naturally produced in the body called interleukin-2 (IL-2), which stimulated them to multiply 1,000-fold. These treated cells could then be injected back into the patient, where they found their way to the tumor and stepped up their attack. “This concept of using the body’s own immune cells as a drug has been the underlying basis of virtually everything I’ve done,” says Dr. Rosenberg.
The first immunotherapies approved for cancer treatment were based upon Dr. Rosenberg’s research with IL-2. In 1985, his team showed that giving patients that hormone could cause tumors to shrink in about 20 percent of people with melanoma and metastatic kidney cancer, with about one-third of those responding to the treatment showing no signs of cancer afterward. The FDA approved IL-2 immunotherapy for kidney cancer in 1992 and for melanoma in 1998.
More recently, Dr. Rosenberg and his team have been developing gene therapies that modify the patient’s own immune cells so that they can more effectively recognize and attack cancer, leading to the 2017 FDA approval of the first-ever gene therapy for cancer. Dr. Rosenberg’s team has also identified hundreds of unique antigens that immune cells could potentially use to identify and attack cancer cells. “These antigens are unique to each individual, so targeting them has to be highly personalized,” he says. Dr. Rosenberg’s team is now working on ways to efficiently produce the modified immune cells needed for this type of treatment and applying it to other cancers such as leukemia and lymphoma.
“This award is a recognition not only of what I’ve done,” Dr. Rosenberg says, “but also an indication and inspiration to continue to make progress toward the goal of developing new immunotherapies for patients with cancer.”
To boost learning, timing may be everything
In a new study, IRP researchers have discovered that transcranial magnetic stimulation (TMS), a noninvasive method of brain stimulation, significantly boosts motor skill learning when precisely administered during specific periods of brain activity.
Groups of neurons in the brain continuously cycle in unison between periods of heightened and suppressed electrical activity called ‘oscillations’ or ‘rhythms.’ When the brain is awake, a cycling of neuronal activity called the ‘mu rhythm’ can be seen in brain regions that are responsible for sensory perception and movement, like the primary motor cortex. Dr. Leonardo Cohen, senior investigator at National Institute of Neurological Disorders and Stroke (NINDS), believes that studying this neuronal rhythm can potentially boost the effects of brain stimulation approaches like TMS, which uses magnetic fields to generate electrical currents in the brain.
The research team led by Dr. Cohen and Dr. Sara Hussain, a former postdoctoral fellow in his lab who is now an assistant professor at the University of Texas at Austin, explored whether delivering TMS during specific phases of neuronal oscillations could enhance learning in a study of 51 individuals practicing a repetitive motor skill task. All participants got better at the task as they practiced on the first and second days of the experiment, however, the participants who had received TMS stimulation only during trough phases of the brain’s mu rhythm improved nearly 50 percent more than the other groups.
“TMS stimulation for therapeutic purposes is usually given regardless of phase,” Dr. Cohen explains. “When we look at our results, we see that TMS during trough phases increases performance by nearly 50 percent, so in reality what researchers are doing right now is a mix of that 50 percent boost when TMS is given during trough phases and the zero percent improvement when TMS is given during peak phases. The mix of those makes the overall size of the effect potentially much smaller.”
Through this research effort, Dr. Cohen hopes to learn how TMS can be more effectively to help patients with neurological problems due to strokes or dementia regain their ability to perform complex movements like walking or grasping objects.
NIH researchers identify how two people controlled HIV after stopping treatment
Researchers at the National Institute of Allergy and Infectious Diseases (NIAID) have identified two methods that individuals with HIV can control the virus for an extended period after stopping antiretroviral therapy (ART) under medical supervision.
The study, led by Dr. Tae-Wook Chun, chief of the HIV Immunovirology Section in the Laboratory of Immunoregulation at NIAID and Dr. Anthony Fauci, NIAID director and chief of the Laboratory of Immunoregulation, involved two adults with HIV who began ART soon after acquiring the virus and continued with treatment to successfully suppress HIV for more than six years. The individuals discontinued ART under a medically supervised HIV clinical trial.
The study team monitored the timing and size of viral rebounds in each participant, that is, times when the amount of HIV in their blood became detectable. One participant suppressed the virus with intermittent rebounds for nearly 3.5 years, at which point he began taking suboptimal ART without informing the study team. The other participant almost completely suppressed HIV for nearly four years, at which point the virus rebounded dramatically because he became infected with a different HIV strain, a phenomenon known as “superinfection.”
The first participant had high levels of HIV-specific immune cells called CD8+ T cells that can kill virus-infected cells while the second participant did not, indicating that different mechanisms of control were at work in each person. The second participant, who had a weaker CD8+ T cell response against HIV, had a very strong neutralizing antibody response throughout the follow-up period until the sudden viral rebound. The scientists hypothesized that neutralizing antibodies may have played a significant role in facilitating near-complete HIV suppression in this individual until he acquired a different strain of the virus. The finding of this study could inform efforts to develop new methods of helping people with HIV put the virus into remission without taking lifelong medication, which can have long-term side-effects.
Buprenorphine misuse decreased among U.S. adults with opioid use disorder from 2015-2019
Buprenorphine is an FDA-approved medication used in the treatment of opioid use disorder and for the relief of severe pain. When used to treat opioid use disorder, buprenorphine works through the partial activation of opioid receptors in the brain, which aids in the reduction of opioid cravings, withdrawal, and overall use of other opioids.
In the National Survey on Drug Use and Health Data, conducted by the National Institute on Drug Abuse (NIDA) and the Centers for Disease Control and Prevention (CDC), nearly three-fourths of adults reporting buprenorphine use in 2019 did not misuse the medication in the past 12 months. Buprenorphine misuse among people with opioid use disorder has been trending downward between 2015-2019, despite increases in the number of people receiving buprenorphine treatment.
In 2020, more than 69,000 people lost their lives due to opioid related drug overdoses. However, in 2019, less than 18% of people with a past-year opioid use disorder received medications to treat their addiction, in part due to stigma and barriers to accessing these medications. Updated guidelines released by the U.S. Department of Health and Human Services in April 2021 has expanded access to buprenorphine for the treatment of opioid use disorder. However, barriers to the use of this treatment remain, including provider unease with managing patients with opioid use disorder, lack of adequate insurance reimbursement, and concerns about risks for diversion, misuse, and overdose.
The study reported roughly 1.7 million people having used buprenorphine as prescribed in the past year, compared with 700,000 people who reported misusing the medication. The study also concluded that people who did not receive treatment for their drug use and those living in rural areas were more likely to misuse the medication, however, being a racial/ethnic minority or living in poverty had no effect on buprenorphine misuse.
“Three-quarters of adults taking buprenorphine do not misuse the drug,” said Dr. Wilson Compton, Deputy Director of NIDA and senior author of the study. “Many people with opioid use disorder want help, and as clinicians, we must treat their illness. The study authors recommended that improvements to the access and quality of buprenorphine treatment for people with opioid use disorder is needed to address the current opioid crisis.
Bipolar disorder is a mental health condition characterized by alternating periods of extreme elation or depression. This unpredictable change in moods and behavior are severe enough to interfere with work, school, and relationships for nearly 90 percent of people affected with bipolar disorder. While as many as 2.3 million Americans have been diagnosed bipolar disorder, it is likely many more people go undiagnosed.
Researchers at the National Institute of Mental Health (NIMH) are transforming our knowledge of bipolar disorder. In a study led by NIH Distinguished Investigator, Dr. Kathleen Merikangas, wearable activity monitors allowed a team of researchers to investigate how sleep and movement affect the moods of people with bipolar disorder and other mood disorders.
“When we studied adolescents in the general population, we learned that one of the most important characteristics of youth who begin to develop bipolar disorder is increased physical activity and energy rather than changes in mood,” explains Dr. Merikangas. In fact, physical activity has now been included as one of the core features in the diagnosis of bipolar disorder. People with this condition are fidgety, restless and moving around a lot even in situations where they would normally sit still.
To further understand the relationships between physical activity, sleep, and mood in patients with bipolar disorder in real-world settings, the research team studied 242 adults with bipolar disorder, major depression, or no history of mood disorders. The study participants wore monitors on their wrists that collected constant, real-time measurements of their activity and sleep duration for two weeks and were given electronic devices programmed with a survey that asked them several times per day to rate their mood and energy level on a scale from one to seven.
The researchers found that participants reported better moods on the survey when they had been more active earlier in the day. A lack of sleep correlated to reduced energy and activity, whereas changes in mood had no impact on energy levels. The influence of sleep and activity on the moods of bipolar participants was much stronger than in those with depression or no mood disorder, and the sleep- and movement-induced boosts in mood and energy level that they experienced took longer to return to more typical levels. As a result of these findings, Dr. Merikangas suggests that increasing physical activity may show promise in the treatment of bipolar disorder.
COVID vaccine booster increases antibody responses, is protective in rhesus macaques
A collaborative research team from Emory University, Bioqual, Moderna, and Johns Hopkins University, led by scientists at the National Institute of Allergy and Infectious Diseases Vaccine Research Center determined that a booster dose of the mRNA-1273 COVID-19 vaccine given to rhesus macaques about six months after their primary vaccine series significantly increased levels of neutralizing antibodies against all known SARS-CoV-2 variants of concern.
This study was conducted six months ago during a time in which the SARS-CoV-2 Beta variant was a major concern. The Beta variant has consistently shown the greatest ability to resist neutralization, likely reducing vaccine effectiveness. While Delta has become the dominant virus variant in the United States due to its high transmissibility, it only has a moderate ability to resist neutralization.
The researchers observed that increased neutralizing antibody responses were sustained for at least eight weeks after the boost. They also generated a higher level of protection by limiting virus replication in the lungs and nose, than after the primary vaccine series. These data suggest that boosting triggers a strong immune memory response and potentially longer lasting immunity.
The researchers concluded that an mRNA-1273 booster vaccine may improve the duration and potency of protection against upper and lower airway infection by any of the circulating SARS-CoV-2 variants. They note that this would be especially important to maintain protection against severe disease and possibly limit mild infection and virus transmission. Their results of the study support vaccine boosting for the elderly, people with pre-existing health conditions, those at high-risk exposure, and those who responded poorly to primary vaccination.
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