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National Institutes of Health (NIH) Research Updates – April 2021

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.

Recent NIH Research

NIH Scientists Redesign Neurons to Enable Targeted Therapies

Genetically modifying neurons has enabled scientists to better understand neuronal communication pathways in the brains of healthy individuals as compared to those with neurological or psychological conditions. Recent advances in technology have furthered the impact of this work, allowing neurologists the ability to target the delivery of drugs to specific brain cells without the side effects resulting from current treatments for these disorders.

In a current study led by Dr. Mike Michaelides, investigator at the National Institute on Drug Abuse (NIDA), the research team used ‘chemogenetics’ to control the firing of specific neurons in the brain. This targeted approach allows the scientists to modify cells and examine specific neurons without resorting to invasive procedures such as electrical stimulation.

In order to study their contributions to a broad range of neurological processes and illnesses, the IRP research team encapsulated customized DNA sequences that code for lab-designed receptors in viral vectors that can deliver the modified genetic material to specific neurons. This tags the neurons for future activation or inhibition. Those selected cells will then start producing the receptor encoded by that DNA, which serves as a docking station for a specially created molecule, called a ligand. Because that ligand can only interact with that lab-designed receptor, it essentially acts as a ‘designer drug’ and can only affect the neurons that the scientists want to target. For that reason, these receptors are referred to as ‘DREADDs’, ‘Designer Receptors Exclusively Activated by Designer Drugs.’

DREADDs are currently used in laboratories around the world to study the brain circuitry behind a number of processes and disorders, such as Parkinson’s disease, pain, and substance abuse. While this technique has allowed researcher to gain insight into the functioning of these neuronal pathways, further work is needed to before these DREADDS will prove useful for human therapies. This is in part due to the weak connections formed between the DREADD receptors and the synthetic ligands that are responsible for their activation. As a result, the tagged cells may interact with other receptors or fail to have the desired effect.

The team of IRP researchers and collaborators are working to fine-tune the DREADD technique by creating new ligands that form stronger bonds with their target DREADD receptors, making their action more potent. In addition, Dr. Michaelides’ team created the first DREADD ‘radioligand,’ a ligand connected to a radioactive isotope that lights up in scans produced by an imaging technology called positron emission tomography (PET). By allowing scientists to track DREADD ligands in the body over time, this new radioligand will make it possible to monitor whether a designer drug hits the right target and whether a certain dose of it binds to enough receptors to induce the desired effect.

“Every time you introduce something foreign into the human body, you want to be able to visualize it,” Dr. Michaelides says. “If you want what you’re injecting to go to a specific part of the body and function correctly, you want to know it’s in the right place. You would also be able to optimize the ligand dose because you could look at the interaction of the ligand with the receptor in real time.”

Dr. Michaelides believes that the first applications of chemogenetic technology in humans will likely be targeting pain relief. This novel approach could alleviate the need for the use of opioids and other medications to control pain.

“There’s a huge problem right now with effective pain medications,” Dr. Michaelides says. “Opioids work well at treating pain, but they have the potential for abuse and other side effects. We want to find a different way of relieving pain more precisely without liability for abuse and with fewer side effects.” While still in pre-clinical development, such a therapy could become available in just a few years.

NIH-led Team Sets New Bar in Retinal Imaging

Age-related macular degeneration (AMD) is a progressive disease caused by the deterioration of the retina. AMD can severely impair vision and is the leading cause of blindness in individuals age 65 and older. Finding new ways to treat and prevent the loss of vision from AMD and related diseases is the focus of a research team at the National Eye Institute (NEI).

A research team led by Dr. Johnny Tam, Stadtman Investigator in NEI’s Clinical and Translational Imaging Unit, visualized the light-sensing cells in the back of the eye, known as photoreceptors, in greater detail than ever before. They were able to improve the imaging resolution by a third by selectively blocking the light used to image the eye. This discovery is the latest in an evolving strategy to monitor cell changes in retinal tissue that will help identify new ways to treat and prevent vision loss resulting from AMD.

There are two types of photoreceptors in the eye, cones and rods, which vary in size and density across the retina. Rod photoreceptors are concentrated along the outer edges of the retina and enable vision in lower light. Cone photoreceptors, while larger than rods, can be difficult to visualize as they are tightly packed together within the fovea, the region of the retina responsible for the highest level of visual acuity and color discrimination. The entire landscape of cones and rods is referred to as the photoreceptor mosaic.

Advanced imaging systems are widely used for observing retinal tissue and are essential tools for diagnosing and studying retinal diseases. But even with adaptive optics retinal imaging, a technique that compensates for light distortions using deformable mirrors and computer-driven algorithms, there are still some areas of the photoreceptor mosaic that are challenging to image, according to Dr. Rongwen Lu, postdoctoral fellow in the Clinical and Translational Imaging Unit at NEI and first author of the paper. “Sometimes rods are hard to image because they are so small,” Lu said. “By eliminating some of the light in the system, it actually makes it easier to see the rods. So, in this case, less is more.”

Dr. Tam’s team at NEI, in collaboration with researchers at Stanford University, Palo Alto, California, sought to push the resolution of adaptive optics retinal imaging further by strategically blocking a portion of the light used to image the retina. Blocking the light that illuminates the eye in the middle of the beam creates a ring of light (rather than a disk), thereby improving the transverse resolution (across the mosaic). However, this coincided with a decrease in axial resolution (mosaic depth). To compensate, the team blocked the light coming back from the eye using a super small pinhole, called a sub-Airy disk, which recovered the axial resolution. The modified technique yielded approximately a 33% increase in resolution, making it much easier to see rods and subcellular details within cones.

“Better imaging resolution will enable better tracking of degenerative changes that occur in retinal tissue. The goal of our research is to discern disease-related changes at the cellular level over time, possibly enabling much earlier detection of disease,” said Dr. Tam. Earlier detection would make it possible to treat patients sooner before vision loss has occurred. The ability to also detect cellular changes would enable clinicians to more quickly determine whether a new therapy is working.

Preterm Birth, Prolonged Labor Influenced by Progesterone Balance

New research by the National Institute of Environmental Health Sciences (NIEHS) found that unbalanced progesterone signals may cause some pregnant women to experience preterm labor or prolonged labor. The study, which was conducted in mice, provides new insights for hormone regulation therapy in late term pregnancy.

During pregnancy, the hormone progesterone helps to prevent the uterus from contracting and going into labor prematurely. This occurs through molecular signaling involving progesterone receptor types A and B, referred to as PGR-A and PGR-B. In this ground-breaking study, NIEHS scientists demonstrated the effects of unbalanced PGR-A and PGR-B signaling on the duration of pregnancy.

Prior research indicated that PGR-A regulates processes involved in initiating childbirth while PGR-B affects molecular pathways related to maintaining the normal course of pregnancy. This current study builds on those findings, revealing that the relative abundance of PGR-A and PGR-B may be critical in promoting healthy pregnancy. The public health implications surrounding this observation are significant.

“We used genetically engineered mouse models to alter the ratio of PGR-A and PGR-B in the muscle compartment of the uterus, called the myometrium,” said Dr. Francesco DeMayo, senior author and head of the NIEHS Reproductive and Developmental Biology Laboratory. “Our team found that PGR-A promotes muscle contraction and PGR-B prevents such contraction, and we identified the biological pathways influenced by both forms.”

Preterm birth affects nearly 10% of all pregnancies and is the leading cause of neonatal morbidity and mortality worldwide, while prolonged labor can result in an increased risk of infection, uterine rupture, and neonatal distress. Care for preterm deliveries can result in high social and economic costs, with infants born preterm at greater risk for experiencing disorders ranging from blindness to cerebral palsy, according to the researchers. Prolonged labor can also harm both mother and infant and lead to cesarean delivery.

“Although labor stimulation by oxytocin infusion is an approved measure to mitigate labor dystocia, serious side effects have been associated with this treatment,” said Dr. Steve Wu, first author on the study and staff scientist in DeMayo’s lab. “Novel proteins that we identified as being part of progesterone signaling could serve as a key molecular switch of uterine contraction, through drug-dependent regulation of their activities.”

“Hormone signaling in pregnancy is complicated and involves both the hormone levels and the types of receptors in the uterus that sense the hormones,” said co-first author Dr. Mary Peavey, department of obstetrics and gynecology at the University of North Carolina at Chapel Hill. “This publication sheds light on how hormones influence labor and can thus be used to help women when the uterus goes into labor too soon or for a prolonged period.”

Study of Mosquito Protein Could Lead to Treatments Against Life-threatening Viruses

Zika, dengue, yellow fever, and West Nile viruses all belong to a family of Flaviviruses that are transmitted via infected ticks and mosquitoes. They are able to replicate and spread within both insects and mammals and can infect humans and domesticated animals, causing significant public health threats.

The mosquito protein AEG12 strongly inhibits Flaviviruses and weakly inhibits coronaviruses, according to scientists at the National Institute of Environmental Health Sciences (NIEHS), and their collaborators. The research team discovered that AEG12 works by destabilizing the viral envelope, breaking its protective covering. Although the protein does not affect viruses that are lacking a viral envelope, the findings from this study could lead to therapeutics against a wide range of disease causing viruses.

To understand more about the structure of AEG12, the scientists used a technique called X-ray crystallography. Dr. Geoffrey Mueller, senior author and head of the NIEHS Nuclear Magnetic Resonance Group, said at the molecular level, AEG12 rips out the lipids, which are the fat-like portions of the membrane that hold the virus together. “It is as if AEG12 is hungry for the lipids that are in the virus membrane, so it gets rid of some of the lipids it has and exchanges them for the ones it really prefers,” Mueller said. “The protein has high affinity for viral lipids and steals them from the virus.”

As a result, AEG12 protein has great killing power over some viruses, says Dr. Mueller. While the researchers demonstrated that AEG12 was highly effective against flaviviruses, it is possible it could also be used to combat SARS-CoV-2, the coronavirus that causes COVID-19. However, it will require further bioengineering to make AEG12 a viable therapy for COVID-19 as it also breaks opens red blood cells. Researchers will have to identify compounds that will make the protein target viruses only.

Dr. Alexander Foo, an NIEHS visiting fellow and lead author of the paper, explained that mosquitoes produce AEG12 when they take a blood meal or become infected with flaviviruses. This results in an elevated immune response against these viruses, with AEG12 rupturing the viral covering. “The prospect of studying a new protein is exciting, yet daunting,” Foo said. “Thankfully, we had enough clues and access to a wide range of expertise at NIEHS to piece it together.”

Study co-author and NIEHS crystallography expert, Dr. Lars Pedersen, routinely uses information about a molecule’s physical characteristics throughout his work and encourages more scientists to consider using this type of data in their studies. He said, “Our research shows that understanding the structure of a protein can be important in figuring out what it does and how it could help treat disease.”

NIH Scientists Use Human Cerebral Organoid to Test Drug for Deadly Brain Disease

In a new study conducted by the National Institute of Allergy and Infectious Diseases (NIAID), scientists have developed a promising new model for the screening of therapeutic drug candidates for the treatment of Creutzfeldt-Jakob disease (CJD). The study was conducted at NIAID’s Rocky Mountain Laboratories in Hamilton, Montana, using a human cerebral organoid system that the team had developed in prior research.

Human cerebral organoids are created using induced pluripotent stem cells derived from skin or blood cells. This three-dimensional organoid model allows researchers to study brain development and disorders in vitro. CJD is a rare, fatal neurodegenerative brain disease of humans caused by infectious prion proteins. The disease can occur spontaneously, result from a hereditary mutation, or arise from contact with infected tissue. A notable example of this occurred in the United Kingdom in the mid-1990s following an outbreak of bovine spongiform encephalopathy in cattle. There are currently no known preventive or therapeutic treatments for CJD.

The lack of a completely human CJD model has been a considerable barrier hindering the discovery of potential therapies. Studies that were effective when conducted in mice failed to translate to viable treatments in human patients. The human cerebral organoid CJD model holds promise that this obstacle can be eliminated. Cerebral organoids have organization, structure, and electrical signaling systems similar to human brain tissue. They are also ideal for long-term studies of nervous system diseases due to their ability to survive in a controlled environment for months or even years. For these reasons, cerebral organoids have been used as models to study Zika virus infection, Alzheimer’s disease, and Down syndrome.

In this study, NIAID Scientists tested pentosan polysulfate (PPS) to determine its potential preventive and therapeutic benefits. In the experiments, PPS treatment reduced the disease indicators by 10-fold or more without causing tissue death. PPS is a benchmark anti-prion compound in laboratory experiments, but it is rarely used clinically because it requires direct administration into the brain.

While it may extend a patient’s life, PPS has not been shown to improve quality of life. However, using the anti-prion properties of PPS with the new human organoid CJD model allowed the researchers to assess the value of this model system for drug discovery. The scientists proved that the human organoid model can effectively be used for the screening of compounds that could potentially be used for preventive treatment.

Such treatment could be used for people carrying genetic mutations that cause the disease, but who have not yet developed symptoms, or for people who may have been exposed to infectious prion proteins that might cause CJD. The model further proved useful for screening drugs against established CJD after a patient has been diagnosed and is already exhibiting disease symptoms.

The research team is working to further develop the organoid model for screening larger numbers of novel drug candidates in the hopes of finding therapeutic treatment options for CJD. They are optimistic that with their fully human model of disease, they can now identify compounds with promise for benefitting patients with CJD.

NIH Scientists Discover How DNA Fragments Can Trigger Inflammation in Sickle Cell Disease

According to a new study from the National Heart, Lung, and Blood Institute (NHLBI), researchers have discovered that mitochondrial DNA acts as a danger signal inside the body and can trigger an inflammatory response in people with sickle cell disease (SCD). These findings could lead to new ways to reduce chronic inflammation in people living with this painful inherited blood disorder.

Normally a red blood cell gets rid of its mitochondria when it matures, because the energy from mitochondria is not needed to carry out the red blood cell’s function of delivering oxygen throughout the body. The research team found that the red blood cells of people with SCD tend to accumulate mitochondria. This condition also allows damaged mitochondrial DNA to enter circulation with too few of the methyl groups that typically attach to the DNA to help the cells function, which could be linked to the excessive inflammation associated with this disease.

“These study findings suggest that measuring DNA of mitochondrial origin could help us better understand its role in pain crises, destruction of red blood cells, and other inflammatory events in sickle cell disease,” said Dr. Swee Lay Thein, chief of the Sickle Cell Branch at NHLBI. “It could also serve as a marker of disease progression and a way to measure the effectiveness of therapeutic interventions.”

Dr. Thein and her staff scientist, Dr. Laxminath Tumburu, the study’s main author, analyzed the complete set of DNA extracted from the blood plasma of 34 people with sickle cell anemia, as well as the blood plasma from eight healthy volunteers. The free-floating mitochondrial DNA from patients with SCD were determined to have fewer methyl groups than were found in the blood plasma of the healthy volunteers. It was also noted that the free-floating mitochondrial DNA from seven of those patients had even less of these methyl groups when the patients were having a pain crisis, as compared to when they were not.

“We were intrigued when we found higher levels of free-floating mitochondrial DNA in the plasma of the patients with sickle cell disease,” said Dr. Thein. “These were shorter and more fragmented than free-floating nuclear DNA fragments, which are also known to drift in the patient’s blood.”

To further examine why this was occurring, the team looked at how the blood plasma containing high levels of free-floating mitochondrial DNA triggers a specific inflammatory process. Neutrophils are part of the immune system and form structures called neutrophil extracellular traps (NETs), that are vital components of the immune response. When a pathogen enters the body, neutrophils circulate in the bloodstream and act as the first line of response. However, a negative consequence of these NETs is inflammation that can be  detrimental, even in the absence of infection. To circumvent this issue, Dr. Thein and her team were able to block the formation of NETs by treating the neutrophils with a small molecule inhibitor.

With this improved understanding of the factors contributing to the sickle cell disease process, the researcher team would like to pursue preclinical testing of drugs that target mitochondrial DNA and the inflammatory process it stimulates in hopes of finding new therapeutic treatments for this disease.

Upcoming Events:

Tuesday, April 13, 2021, 11:00 am to Wednesday, April 14, 2021, 4:00 pm (registration required)
Machine Learning in Genomics: Tools, Resources, Clinical Applications and Ethics

Wednesday, April 14, 2021 to Friday, April 16, 2021 (register by April 9)
National Cancer Institute RNA Biology Symposium

Tuesday, April 27, 2021 to Thursday, April 29, 2021
2021 Virtual Postbac Poster Day

National Center for Complementary and Integrative Health (NCCIH) Events:

Friday, June 18, 2021

Assessing and Measuring Target Engagement: Mechanistic and Clinical Outcome Measures for Brain Disorders of Aging

Wednesday, August 25, 2021

Relating Target Engagement to Clinical Benefit: Biomarkers for Brain Disorders of Aging