Research advances from the National Institutes of Health (NIH) Intramural Research Program (IRP) often make headlines. Read the news releases that describe our most recent findings:
Proof-of-concept study analyzed a newer technology known as single-cell RNA sequencing
In a proof-of-concept study, researchers at the National Institutes of Health (NIH) have developed an artificial intelligence (AI) tool that uses data from individual cells inside tumors to predict whether a person’s cancer will respond to a specific drug. Researchers at the National Cancer Institute (NCI), part of NIH, published their work on April 18, 2024, in Nature Cancer, and suggest that such single-cell RNA sequencing data could one day be used to help doctors more precisely match cancer patients with drugs that will be effective for their cancer.
Current approaches to matching patients to drugs rely on bulk sequencing of tumor DNA and RNA, which takes an average of all the cells in a tumor sample. However, tumors contain more than one type of cell and in fact can have many different types of subpopulations of cells. Individual cells in these subpopulations are known as clones. Researchers believe these subpopulations of cells may respond differently to specific drugs, which could explain why some patients do not respond to certain drugs or develop resistance to them.
In contrast to bulk sequencing, a newer technology known as single-cell RNA sequencing provides much higher resolution data, down to the single-cell level. Using this approach to identify and target individual clones may lead to more lasting drug responses. However, single-cell gene expression data are much more costly to generate than bulk gene expression data and not yet widely available in clinical settings.
NIH scientists use artificial intelligence called ‘P-GAN’ to improve next-generation imaging of cells in the back of the eye
Researchers at the National Institutes of Health applied artificial intelligence (AI) to a technique that produces high-resolution images of cells in the eye. They report that with AI, imaging is 100 times faster and improves image contrast 3.5-fold. The advance, they say, will provide researchers with a better tool to evaluate age-related macular degeneration (AMD) and other retinal diseases.
“Artificial intelligence helps overcome a key limitation of imaging cells in the retina, which is time,” said Johnny Tam, Ph.D., who leads the Clinical and Translational Imaging Section at NIH's National Eye Institute.
Tam is developing a technology called adaptive optics (AO) to improve imaging devices based on optical coherence tomography (OCT). Like ultrasound, OCT is noninvasive, quick, painless, and standard equipment in most eye clinics.
NIH-supported clinical trial could lead to first effective treatment for ACDC disease
A drug used to treat certain bone diseases shows promise for slowing the progression of a rare, painful genetic condition that causes excessive calcium buildup in the arteries, known as arterial calcification due to deficiency of CD73 (ACDC). These results are from a first-in-human clinical trial supported by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health. The study, published in the journal Vascular Medicine, could lead to the first effective treatment for the rare disease.
ACDC, which has no known cure, often targets the arteries of the legs and can make walking painful and difficult. It can also affect the joints of the hands, causing pain and deformities. In severe cases, the condition can lead to potential limb loss. Symptoms of the disease often begin in the late teens and 20s. An extremely rare disease, it is believed to affect only about 20 people worldwide and has an estimated prevalence of less than 1 in 1 million. Previous studies have identified the gene for ACDC disease and the biochemical mechanism behind it. More recent studies by the NHLBI research team identified an existing drug, called etidronate, as a potential treatment for ACDC based on disease models in animals and human cells.
In the study, researchers evaluated the safety and effectiveness of etidronate in treating calcification of the arteries and impaired blood flow in the legs of seven people (four women and three men) with ACDC disease. Although few, they collectively represent about one-third of all the known cases in the world. Treatment consisted of taking the oral drug daily for 14 days every three months over a three-year period. The researchers measured calcium deposits using CT scans and tested blood flow using the ankle brachial index, a non-invasive tool, both at the start of the study and as a yearly follow-up after treatment.
A CT angiography scan of a person with ACDC disease showing abnormal calcification of the blood vessels in the legs and feet.
NIH-supported study also found Black people with depression used different language compared to white people to express their thoughts on Facebook
Researchers were able to predict depression severity for white people, but not for Black people using standard language-based computer models to analyze Facebook posts. Words and phrases associated with depression, such as first-person pronouns and negative emotion words, were around three times more predictive of depression severity for white people than for Black people. The study, published today in the Proceedings of the National Academy of Sciences, is co-authored by researchers at the University of Pennsylvania, Philadelphia, and the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health (NIH), which also funded the study.
While previous research has indicated that social media language could provide useful information as part of mental health assessments, the findings from this study point to potential limitations in generalizing this practice by highlighting key demographic differences in language used by people with depression. The results also highlight the importance of including diverse pools of data to ensure accuracy as machine learning models, an application of artificial intelligence (AI) language models, are developed.
“As society explores the use of AI and other technologies to help deliver much-needed mental health care, we must ensure no one is left behind or misrepresented,” said Nora Volkow, M.D., NIDA director. “More diverse datasets are essential to ensure that healthcare disparities are not perpetuated by AI and that these new technologies can help tailor more effective health care interventions.”
Treatment for rare childhood disease was well tolerated and slowed loss of motor function
An investigational gene therapy for a rare neurodegenerative disease that begins in early childhood, known as giant axonal neuropathy (GAN), was well tolerated and showed signs of therapeutic benefit in a clinical trial led by the National Institutes of Health (NIH). Currently, there is no treatment for GAN and the disease is usually fatal by 30 years of age. Fourteen children with GAN, ages 6 to 14 years, were treated with gene transfer therapy at the NIH Clinical Center and then followed for about six years to assess safety. Results of the early-stage clinical trial appear in the New England Journal of Medicine.
The gene therapy uses a modified virus to deliver functional copies of the defective GAN gene to nerve cells in the body. It is the first time a gene therapy has been administered directly into the spinal fluid, allowing it to target the motor and sensory neurons affected in GAN. At some dose levels, the treatment appeared to slow the rate of motor function decline. The findings also suggest regeneration of sensory nerves may be possible in some patients. The trial results are an early indication that the therapy may have favorable safety and tolerability and could help people with the rapidly progressive disease.
“One striking finding in the study was that the sensory nerves, which are affected earliest in GAN, started ‘waking up’ again in some of the patients,” said Carsten G. Bonnemann, M.D., senior author and chief of the Neuromuscular and Neurogenetic Disorders of Childhood Section at the National Institute of Neurological Disorders and Stroke (NINDS), part of NIH. “I think it marks the first time it has been shown that a sensory nerve affected in a genetic degenerative disease can actually be rescued with a gene therapy such as this.”
Biopsy of a sensory nerve from a participant in the GAN gene therapy trial (arrows indicate giant axons; regenerating nerve cluster in upper left). Some patients regained sensory nerve response after treatment.
The drug minocycline, an antibiotic that also decreases inflammation, failed to slow vision loss or expansion of geographic atrophy in people with dry age-related macular degeneration (AMD), according to a phase II clinical study at the National Eye Institute (NEI), part of the National Institutes of Health.
Dry AMD affects the macula, the part of the eye’s retina that allows for clear central vision. In people with dry AMD, patches of light-sensing photoreceptors and their nearby support cells begin to die off, leaving regions known as geographic atrophy. Over time, these regions expand, causing people to lose more and more of their central vision. Microglia, immune cells that help maintain tissue and clear up debris, are present at higher levels around damaged retinal regions in people with dry AMD than in people without AMD. Scientists have suggested that inflammation — and particularly microglia — may be driving the expansion of geographic atrophy regions.
This study, led by Tiarnan Keenan, M.D., Ph.D., a Stadtman Tenure-Track Investigator at the NEI’s Division of Epidemiology and Clinical Applications, tested whether inhibiting microglia with minocycline might help slow geographic atrophy expansion and its corresponding vision loss. The trial enrolled 37 participants at the NIH Clinical Center in Bethesda, Maryland, and at the Bristol Eye Hospital, United Kingdom. After a nine-month period where the researchers tracked each participant’s rate of geographic atrophy expansion, the participants took twice-daily doses of minocycline for two years. The researchers compared each participant’s rate of geographic atrophy expansion while taking minocycline to their baseline rate, and found there was no difference in geographic atrophy expansion rate or vision loss with minocycline.
Retina, showing a large region of geographic atrophy.
Compared to healthy volunteers, affected U.S. government personnel did not exhibit differences that would explain symptoms
Using advanced imaging techniques and in-depth clinical assessments, a research team at the National Institutes of Health (NIH) found no significant evidence of MRI-detectable brain injury, nor differences in most clinical measures compared to controls, among a group of federal employees who experienced anomalous health incidents (AHIs). These incidents, including hearing noise and experiencing head pressure followed by headache, dizziness, cognitive dysfunction and other symptoms, have been described in the news media as 'Havana Syndrome' since U.S. government personnel stationed in Havana first reported the incidents. Scientists at the NIH Clinical Center conducted the research over the course of nearly five years and published their findings in two papers in JAMA today.
“Our goal was to conduct thorough, objective and reproducible evaluations to see if we could identify structural brain or biological differences in people who reported AHIs,” said Leighton Chan, M.D., chief, rehabilitation medicine and acting chief scientific officer, NIH Clinical Center, and lead author on one of the papers. “While we did not identify significant differences in participants with AHIs, it’s important to acknowledge that these symptoms are very real, cause significant disruption in the lives of those affected and can be quite prolonged, disabling and difficult to treat.”
Researchers designed multiple methods to evaluate more than 80 U.S. government employees and their adult family members, mostly stationed abroad, who had reported an AHI and compared them to matched healthy controls. The control groups included healthy volunteers who had similar work assignments but did not report AHIs. In this study, participants underwent a battery of clinical, auditory, balance, visual, neuropsychological and blood biomarkers testing. In addition, they received different types of MRI scans aimed at investigating volume, structure and function of the brain.
Large study finds atypical interactions between the frontal cortex and information processing centers deep in the brain
Researchers at the National Institutes of Health (NIH) have discovered that symptoms of attention-deficit/hyperactivity disorder (ADHD) are tied to atypical interactions between the brain’s frontal cortex and information processing centers deep in the brain. The researchers examined more than 10,000 functional brain images of youth with ADHD and published their results in the American Journal of Psychiatry. The study was led by researchers at NIH’s National Institute of Mental Health (NIMH) and National Human Genome Research Institute (NHGRI).
Luke Norman, Ph.D., a staff scientist in the NIMH Office of the Clinical Director, and colleagues analyzed brain images supplied by more than 8,000 youth with and without ADHD sourced from six different functional imaging datasets. Using these images, the researchers examined associations between functional brain connectivity and ADHD symptoms.
They found that youth with ADHD had heightened connectivity between structures deep in the brain involved in learning, movement, reward, and emotion (caudate, putamen, and nucleus accumbens seeds) and structures in the frontal area of the brain involved in attention and control of unwanted behaviors (superior temporal gyri, insula, inferior parietal lobe, and inferior frontal gyri).
New details of EBV protein could aid treatment, prevention efforts
Studies of interactions between two lab-generated monoclonal antibodies (mAbs) and an essential Epstein-Barr virus (EBV) protein have uncovered targets that could be exploited in designing treatments and vaccines for this extremely common virus. The research was led by Jeffrey I. Cohen, M.D., and colleagues from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. Study findings were published in the journal Immunity.
Approximately 95% of the world’s population is infected with EBV, which remains in the body permanently, typically in B lymphocytes, which are antibody-producing immune system cells, and cells lining the throat and pharynx. EBV can sometimes lead to B-cell cancers, including Burkitt, Hodgkin and non-Hodgkin lymphomas, or to gastric or nasopharyngeal cancers. Recently, EBV infection was shown to significantly raise the risk of developing multiple sclerosis. There is no vaccine to prevent EBV infection nor a specific treatment.
In this study, NIAID investigators examined a viral protein called gp42, which the virus must use to infect B cells. Theoretically, a vaccine or antibody-based treatment capable of blocking gp42’s ability to bind to or fuse with B cells would prevent EBV infection and, thus, the virus’s ability to persist in those cells. The team generated two gp42-specific mAbs, A10 and 4C12, and used X-ray crystallography to visualize how they interacted with gp42. The crystal structures revealed that the two mAbs interacted with distinct, non-overlapping sites on gp42. Monoclonal antibody A10 blocked the site on gp42 required for receptor binding, while 4C12 interfered with a different site that is involved in membrane fusion.
An electron micrograph showing three Epstein-Barr virus (EBV) particles colorized pink.
NIH-led study sheds light on the causes of new cancers among childhood cancer survivors and could have implications for their screening and follow-up
Common inherited genetic factors that predict cancer risk in the general population may also predict elevated risk of new cancers among childhood cancer survivors, according to a study led by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health. The findings, published in Nature Medicine, provide additional evidence that genetics may play an important role in the development of subsequent cancers in survivors of childhood cancer and suggest that common inherited variants could potentially inform screening and long-term follow-up of those at greatest risk.
Childhood cancer survivors are known to have a higher risk of developing a new cancer later in life due to adverse effects of cancer treatment or rare inherited genetic factors. In the new study, the researchers evaluated the combined effect of common variants with history of radiation treatment and found the resulting elevated cancer risk was greater than the sum of the individual associations for treatment and genetic factors alone.
“Knowledge about a person’s genetic makeup could potentially be useful in managing their risk of subsequent cancers,” said lead investigator Todd M. Gibson, Ph.D., of NCI’s Division of Cancer Epidemiology and Genetics. “The hope would be that, in the future, we can incorporate genetics along with treatment exposures and other risk factors to provide a more complete picture of a survivor’s risk of subsequent cancers to help guide their long-term follow-up care.”
