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 scientific research through its Intramural Research Program (IRP). It 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.

Recent NIH Research

Bringing Out the Big Guns Against Blood Cancer

Acute myeloid leukemia (AML) is a highly fatal blood cancer with a high relapse rate. AML patients in remission receive bone marrow transplants to replace diseased ones with healthy ones. However, the procedure has a high failure rate.

Senior IRP investigator Dr. Christopher Hourigan, M.D., D.Phil., has made it his mission to find ways to detect, prevent, and treat AML recurrence. His team is working on developing clinical tools to help doctors make informed decisions about the best treatments for their patients.

Dr. Hourigan and his team studied pre-transplant blood samples from adults with AML who participated in a 2011 NIH-funded Bone and Marrow Transplant Clinical Trials Network study, which compared low and high-intensity preparative therapy for patients in clinical remission. Findings from this initial study quickly showed that less intensive transplants were not as successful at preventing relapse and ended early. Even though the research ended early, his team viewed it as an opportunity to look for biological indicators linked to a higher risk of relapse in AML patients.

“To us, it seemed like the perfect trial to ask that question,” Dr. Hourigan says. “Our hypothesis was that the outcome would be bad mainly for those patients with trace levels of leukemia left after chemotherapy who then received a reduced-intensity transplant. It’s pretty simple but answering the question in a definitive way requires a large randomized clinical trial with hundreds of patients.”

His team discovered that people who had any indication of leukemia cells before a less-intensive transplant were more likely to relapse than those treated with an intensive transplant. However, patients with no residual signs of AML before receiving a less-intense procedure had the same low risk of relapse as those given an intensive transplant.

“I think there are two implications from the findings,” Dr. Hourigan says. “One is that we probably shouldn’t use reduced-intensity transplants, when possible, in people who have detectable residual leukemia. The other point that I think really sparked people’s imagination is the idea that still having measurable residual disease after initial treatment is not just fate. There’s a tangible thing we as doctors can do to improve the outcomes.”

Dr. Hourigan’s lab has been working to see if changes could be made to the clinical standard of care for leukemia patients by using genomic tests that are much more sensitive and can detect very low numbers of cancer cells. The first stage of this project, dubbed Pre-MEASURE, examined banked pre-transplant blood samples from patients in remission and discovered evidence of residual cancer cells strongly linked to later relapse. His group and its collaborators are conducting a more extensive multi-center study, MEASURE, to see if this testing can be incorporated into clinical practice across the country.

“I think there has been incredible value for our intramural laboratory to collaborate with clinical networks outside NIH to add value to the efforts they are already making by adding an initial layer of scientific investigation,” Dr. Hourigan says. “I think that, for my program, specifically, this is a model of how we’re going to go forward. It’s a win-win for everyone. It’s great for us in that we have access to relevant, clinically annotated, important samples with meaningful outcomes, and it’s great for the bone marrow transplant community because they get extra value from the clinical work and trials that have already been done. Most importantly, it is better for patients who will ultimately have more accurate information on the status of their cancer after initial treatment and personalized, evidence-based advice on what best to do next.”

Novel imaging approach reveals important details about rare eye disease choroideremia

Researchers at the National Eye Institute have used traditional eye imaging techniques and adaptive optics to show how different eye tissue layers are affected in people with choroideremia for the first time.

Choroideremia is a rare degenerative eye disease caused by a mutation in a gene on the X chromosome that disrupts these tissues to a previously unseen degree. The condition is more common in males because they only have one copy of the X chromosome, resulting in more severe symptoms.

Johnny Tam, Ph.D., head of the NEI Clinical and Translational Imaging Unit, and his team looked at live cells in the retina, including light-sensitive photoreceptors and retinal pigment epithelium (RPE) and choroidal blood vessels, to see how choroideremia affects these tissues in detail, providing insights that may be used to develop treatments for other illnesses.

“One major finding of our study was that the RPE cells are dramatically enlarged in males and females with choroideremia,” said Tam. “We were surprised to see many cells enlarged by as much as five-fold.”

Their study showed that female participants had a mix of enlarged and healthier-looking RPE cells, which is likely why women with choroideremia tend to have milder symptoms overall. However, the photoreceptor and blood vessel layers were less affected in male and female study participants, suggesting that the RPE disruption plays a more vital role in choroideremia than previously thought.

While Tam’s adaptive optics is not a regular part of eye clinic diagnostic testing, his team found that enlarged RPE cells can be detected using commercially available scanning laser ophthalmoscope and indocyanine green dye.

“It’s not obvious at first, but using an existing tool in the clinic, we can monitor and track the cellular status of the RPE layer. This could prove valuable in identifying which patients would benefit the most from therapeutic interventions,” said Tam.

With this new information, better treatments can be designed for this disease and others.

Overzealous Immune Cells Hamper Healing

Diabetic foot ulcers (DFUs) are a severe complication of diabetes that can lead to reduced quality of life and high mortality rates. DFUs are characterized by a deregulated immune response with decreased neutrophils due to the loss of the transcription factor FOXM1. Diabetes primes neutrophils to form neutrophil extracellular traps (NETs), contributing to tissue damage and impaired healing.

“The main reason that NET production occurs is to prevent the spread of infection, but when there are excessive amounts of NETs, it can damage the tissue,” said Andrew Sawaya, Ph.D., who led the new study as a postdoctoral fellow in the lab of IRP senior investigator Maria Morasso, Ph.D., “What’s impairing wound healing is too much NET production.”

The new study from IRP researchers found that FOXM1 controls neutrophil ROS levels and inhibition of FOXM1 cause an increase in ROS, resulting in NET formation. They discovered that a gene called TREM1, typically highly active in neutrophils, was less involved in DUFs. Furthermore, they found that TREM1 expression was linked with DFU clinical healing outcomes, suggesting that TREM1 may be used as a biomarker or a potential therapeutic target.

“Right now, it takes four or five weeks for clinicians to know whether their patients are healers or non-healers,” Dr. Morasso says. “Knowing a month ahead of time is a very big advantage for patients and clinicians.”

Their study revealed the clinical importance of TREM1 and suggests that the FOXM1 pathway has a role in regulating NET formation during diabetic wound healing. This could lead to novel therapeutic strategies for promoting healing in DFUs. However, before developing such therapies, Dr. Morasso’s team and other scientists must first understand how TREM1, FOXM1, and NET production interact during the healing process.

“We know that TREM1 is active in other types of cells that are very important not only for normal wound healing, but also in the context of diabetic non-healing wounds,” Dr. Morasso says. “The more we know about how TREM1 is doing this, the better able we’ll be to apply it for therapeutics.”

A healthy lifestyle may help former smokers lower their risk of death from all causes

Previous research has shown that individuals who follow healthy lifestyle recommendations such as maintaining healthy body weight, being physically active, eating a nutritious diet, and limiting alcohol consumption have a reduced risk of illness and death. Quitting smoking has been linked to several health advantages. People who have previously smoked have a greater chance of disease and death than those who have never done so. However, few studies have investigated the significance of living a healthy lifestyle among former smokers.

A new study by researchers at NCI found that maintaining a healthy lifestyle—which includes regular physical activity and eating nutritiously—was linked to reducing the risk of death by 27% over 19 years, compared with not living healthily. The findings come from an analysis of a large group of former smokers who participated in the NIH-AARP Diet and Health Study.

“I was surprised to see the robust associations [with lifestyle],” said Maki Inoue-Choi, Ph.D., of the Division of Cancer Epidemiology and Genetics at NCI, lead author of the paper. “Former smokers who adhered to evidence-based recommendations for body weight, diet, physical activity, and alcohol intake had a lower risk of mortality than former smokers who didn’t adhere to these recommendations.”

Researchers calculated a total adherence score ranging from none to full adherence. Participants with the most significant total adherence scores had a 27% reduced risk of death from any cause than those with the lowest scores. Furthermore, individuals with the best scores had a 24% lower risk of dying from cancer, a 28% reduction in the chance of dying from heart disease, and a 30% decreased risk of respiratory failure.

“To have the greatest benefit, it is better to adhere to many lifestyle recommendations,” Dr. Inoue-Choi noted. “But even those who adopted a single lifestyle recommendation experienced benefits.”

The researchers noted that studies that rely on self-reported information could only reveal delicate relationships, not develop hypotheses about causality. Although the team controlled many variables that could have influenced their findings, they said other factors might be at play.

Heart medication shows potential as treatment for alcohol use disorder

There are three approved medications for alcohol use disorder in the United States. While effective, treatment options must be broader to target the diverse biological processes contributing to this condition. A recent study by scientists at the National Institute on Drug Abuse (NIDA) and Yale School of Medicine in New Haven, Connecticut, suggests that spironolactone, a medication, may play a part in decreasing alcohol consumption.

Spironolactone blocks mineralocorticoid receptors, and past research has revealed that mineralocorticoid receptors, located in various parts of the brain and other organs, might help manage fluid and electrolyte balance in the human body. These could also play a role in alcohol use and cravings. Furthermore, preclinical studies point to greater mineralocorticoid receptor activity leading to increased alcohol consumption.

“Combining findings across three species and different types of research studies and then seeing similarities in those data gives us confidence that we are onto something potentially important scientifically and clinically. These findings support further study of spironolactone as a potential treatment for alcohol use disorder. This medical condition affects millions of people in the U.S,” said Lorenzo Leggio, M.D., Ph.D., chief of the Clinical Psych neuroendocrinology and Neuropsychopharmacology Section, a joint laboratory of NIDA and NIAAA and one of the senior authors.

NIAAA and NIDA researchers found that spironolactone, when given in increasing doses to male and female mice and rats that engage in excessive alcohol drinking, decreases the animals’ alcohol consumption levels without any adverse side effects. In another study conducted in collaboration with this team, researchers found that spironolactone treatment significantly reduced self-reported alcohol consumption, as measured by the Alcohol Use Disorders Identification Test-Consumption.

“These are very encouraging findings,” said NIAAA Director George F. Koob, Ph.D., a co-author of the study. “Taken together, the present study argues for conducting randomized, controlled studies of spironolactone in people with alcohol use disorder to further assess its safety and potential efficacy in this population, as well as additional work to understand how spironolactone may reduce alcohol drinking.”

Genomics study identifies unique set of proteins that restores hearing in zebrafish

Hearing loss affects around 37.5 million Americans, and most cases come from the loss of hearing receptors known as “hair cells” in the inner ear. Although hair cell loss cannot be reversed in people, many species, such as zebrafish, may recover hearing by regenerating hair cells. Because zebrafish and humans have 70% of their genes in common, researchers from the National Institutes of Health were intrigued by the regenerative potential of the fish and its hair cells.

Dr. Erin Jimenez, a postdoctoral fellow in the laboratory of Dr. Shawn Burgess – a senior investigator in the National Human Genome Research Institute’s (NHGRI) Translational and Functional Genomics Branch – led the study with help from researchers Ivan Ovcharenko, Ph.D., and Wei Song, Ph.D., at NLM’s National Center for Biotechnology Information.

“Humans and other mammals are born with a set number of hair cells that are slowly lost through aging and trauma. However, some animals, such as zebrafish, can regenerate hair cells and recover hearing after injury,” said Burgess, “How and why regeneration happens in these animals remains a mystery that many scientists would like to unravel.”

Using new genomic techniques and a single-cell assay for transposase-accessible chromatin using sequencing, Jimenez and her study collaborators discovered that hair cell regeneration in zebrafish depends on a network of proteins called transcription factors, which can turn genes on and off.

“Our study identified two families of transcription factors that work together to activate hair cell regeneration in zebrafish, called Sox and Six transcription factors,” said Jimenez.

Hair cells die in zebrafish when their stem cells are damaged, causing adjacent support cells to proliferate. These support cells are similar to stem cells since they can differentiate into other cell types. Researchers have identified some switches that turn on and coordinate genes encoding those factors with various unknown elements, but not how or where they activate.

“We have identified a unique combination of transcription factors that trigger regeneration in zebrafish. Further down the line, this group of zebrafish transcription factors might become a biological target that may lead to developing a novel therapy to treat hearing loss in humans,” Jimenez said.

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Irreducible Subjects: Disability and Genomics in the Past, Present, and Future 

Thursday, October 6, 2022, 10:00 am to Friday, October 7, 2022, 5:00 pm (registration required)

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