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National Institutes of Health (NIH) Research Updates – August 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

Experimental Compound Supercharges Cellular Power Plants

In a recent IRP study, researchers have identified a novel therapeutic strategy that could aid in treating obesity and related metabolic diseases, such as heart disease and diabetes, through increased cellular energy production. Mitochondria, first coined the “the powerhouse of the cell” by Philip Siekevitz in 1957, provides most of our cells’ supply of energy in the form of adenosine triphosphate (ATP). The regulation of the synthesis and degradation of ATP to ADP is carried out by AMPK (5′ AMP-activated protein kinase), an enzyme that is activated when cellular energy supplies are low. This master regulator protein increases mitochondrial energy production during times of metabolic stress such as low carbohydrate levels. To further reach a state of cellular homeostasis, AMPK elevates mitophagy activity, which acts as a quality control mechanism that degrades mitochondria that are damaged or no longer required.

Why mitochondrial dysfunction occurs, less energy is being produced and reactive oxygen species (ROS) are created that cause cellular damage. This is a serious concern particularly in individuals with obesity. Since AMPK only ramps up mitophagy when energy is scarce, their abundant stores of energy in the form of body fat and excess glycogen, a form of sugar, depress AMPK activity.

“One of the problems that occurs with obesity is, because there’s such a surplus of energy, mitochondria production, as well as quality control, declines because you don’t need those energy factories to be working very efficiently or very hard,” says Dr. Jay Chung, senior investigator at the NHLBI’s Laboratory of Obesity and Aging Research. “The cell pays less attention to mitochondria because it doesn’t need them as much, and when you neglect the quality control of mitochondria, you get an accumulation of damaged mitochondria, which can produce ROS and cause many of the diseases that stem from obesity: diabetes, heart disease, and so forth.”

The drugs that are currently in use for the treatment of those diseases through the direct activation of AMPK cause side effect that can pose serious health risks, such as the enlargement of the heart that can potentially lead to heart failure. Through a prior IRP study, Dr. Chung’s research team discovered an alternative route for the activation AMPK. They found that inhibiting an enzyme called PDE4 (Phosphodiesterase-4), caused an increase in AMPK and mitophagy activity, resulting in improved mitochondrial function, increased physical stamina, and blood sugar regulation in mice, providing protection from diet-induced obesity. Unlike other PDEs, PDE4 is not present in the heart, so drugs that target it should not cause the same heart problems as the direct AMPK activators.

To test this theory, Dr. Chung collaborated with a team of organic chemists to synthesize several brand-new molecules whose structures suggested they could inhibit PDE4. Subsequent tests revealed that one of these compounds, named CBU91, only inhibited PDE4 and not its close cousins, and it was also much more effective at inhibiting PDE4 than the drug Dr. Chung’s lab used in its prior study.

Using myotubes, collections of cells that closely resemble muscle fibers, the research team found that CBU91 increased AMPK and mitophagy activity, resulting in a greater ability for the treated cells to burn fat molecules for fuel. The CBU91 treated myotubes also had much higher levels of messenger RNA molecules, used to increase production of the PGC1-alpha protein, an enzyme that drives the production of new mitochondria. Due to the fact that AMPK activity increases when cells die, the researchers conducted tests to validate that the cells treated with CBU91 were not dying at a faster rate that the untreated cells.

The higher amount of healthy mitochondria that are present in cells, the greater the body’s ability to burn fat and regulate blood sugar, making drugs with effects like those of CBU91 extremely promising as treatments for obesity and diabetes. They may also have potential for treating Alzheimer’s disease as the buildup of dysfunctional mitochondria in neurons is present in that illness as well. In future studies, Dr. Chung plans to investigate which types of PDE4 are present in various bodily tissues and develop compounds that inhibit only specific forms of it to reduce potential side effects.

A Record-Breaking Sprint to Create a COVID-19 Vaccine

December 2019 marks the start of what would quickly become a global pandemic, with the first human cases of this “pneumonia-like” illness originating in Wuhan, China. By January 2020, Chinese scientists had isolated a new coronavirus, SARS-CoV-2, that was responsible for causing this serious epidemic. When the genetic sequence was released to the worldwide scientific community, viral immunologists, Dr. Barney Graham, director of the VRC’s Viral Pathogenesis Laboratory (VPL) and Dr. Kizzmekia Corbett, VRC research fellow, immediately began working on a vaccine for the illness that would become known as COVID-19.

“Dr. Corbett was directing a team doing coronavirus work, and we had relationships with three or four really good academic collaborators and had been having monthly conference calls for years,” Dr. Graham says. “We also had our industry collaborators, and we had a strategy and all the technology, so we were ready to go.”

Dr. Graham and Dr. Corbett quickly developed their plan of attack. The team went to work on designing an antigen, a copy of the spike protein found on the surface of the COVID-19 virus which it uses to infect cells. After years of prior work on coronaviruses, along with their partners at Moderna, the research team perfected a method to coax the body to manufacture antigens via messenger RNA (mRNA). Within 48 hours after the release of the coronavirus’ genome, the team had designed the protein that would be used for their candidate COVID-19 vaccine. The VRC then began clinical trials in collaboration with Moderna and clinical investigators from NIH’s Division of Microbiology and Infectious Diseases (DMID). Ultimately, the vaccine received emergency use authorization from the U.S. Food and Drug Administration (FDA) on December 18, 2020, just one week after a similar vaccine developed by Pfizer.

In recognition of this groundbreaking success in developing a life-saving COVID-19 vaccine in record time, Dr. Graham and Dr. Corbett were named finalists for the 2021 Samuel J. Heyman Service to America Medals, also known as the ‘Sammies.’ Often referred to as the ‘Oscars of government service,’ the Sammies honor exceptional work by government employees.

While creation of the specific vaccine for COVID-19 was surprisingly fast, Dr. Graham and Dr. Corbett, along with fellow researchers in their field, had been laying the groundwork for decades. In Dr. Graham’s prior studies on respiratory syncytial virus (RSV), a vaccine prepared from inactivated virus actually caused the disease to worsen in children who received it. Dr. Graham discovered that the original RSV vaccine induced a response from immune cells creating an allergic-type reaction, making a lot of mucus and not effectively clearing the virus from the body. Inactivating the virus also caused it to change shape to the form it takes once it has already infected and fused with a cell. As a result, the vaccine caused the body to release antibodies that could bind to the virus but could not block infection, making it ineffective. These findings provided the foundation for him to create vaccines that could emulate the pre-fusion form of the virus.

Dr. Graham continued the RSV project in 2000 when he was recruited to the NIH to help create the VRC. He and Dr. Jason McLellan, a postdoctoral fellow in the lab of IRP senior investigator Dr. Peter Kwong, isolated and created 3D models of the pre-fusion RSV virus protein. The resulting vaccine using the pre-fusion model of the virus enabled the body to produce antibodies that were 16 times more potent than the original vaccine. The discovery of the pre-fusion structure proved foundational to the work Dr. Graham’s lab subsequently began on coronaviruses such as SARS and MERS. “After we had the RSV breakthrough, Dr. McLellan and I decided that coronaviruses were similar enough to RSV and there was no structural information for them,” Dr. Graham says. “That was a good area to work in because it was a wide-open field and it needed to be done.”

In 2014, Dr. Corbett joined the VPL as a senior research fellow and focused her work on understanding the mechanism that antibodies use to bind to different forms of coronavirus spike proteins to block infection. She also began work on a method for quickly and reliably developing antigen proteins to match each virus and to deliver the instructions for making these proteins to cells via mRNA.

The VRC was already gearing up for clinical trials with Moderna to test an mRNA vaccine against Nipah virus, which the lab had developed in parallel with an mRNA vaccine against the coronavirus that caused the 2012 MERS outbreak. As a result, by the time COVID-19 emerged, the VPL was well positioned to switch gears to a vaccine for COVID-19 and hit the ground running.

With the race to develop a safe and effective COVID-19 vaccine winding down, both Dr. Graham and Dr. Corbett are planning their future endeavors. Dr. Graham hopes to retire at the end of the year and devote time to improving communication and education about science and technology, particularly in low- and middle-income countries. In June, Dr. Corbett left the NIH to lead her own laboratory at Harvard University’s T.H. Chan School of Public Health, where she plans to continue her work on coronaviruses. She is also working to educate the public about vaccination and addressing vaccine hesitancy, particularly in communities of color, and hopes to inspire young people to pursue careers in science.

Words Matter: Language can Reduce Mental Health and Addiction Stigma, NIH Leaders Say

People with mental illness and substance addiction have long been stigmatized throughout society arising from their inability to adhere to social norms. Public education, training of healthcare professionals, and advancements in medicine have aided in reducing the stigma surrounding these conditions but further efforts are needed. In a recent article published in Neuropsychopharmacology, NIH leaders discuss how using the appropriate language to describe mental illness and addiction helps to reduce stigma, thereby improving how individuals with these conditions are treated within the health care system and throughout society. The words we use can also impact the likelihood that these individuals will seek out treatment and of the quality of care that they may receive. Findings from over a decade of research concludes that stigma associated with mental illness or a substance abuse disorder can result in negative health outcomes and creates a barrier to seeking treatment.

Statistics show that nearly 35% of people in the US with serious mental illness conditions and approximately as high as 90% of people having substance abuse disorders, do not receive treatment for their conditions. The authors, Dr. Nora Volkow, NIDA Director, Dr. Joshua Gordon, NINDS Director, and Dr. George Koob, NIAAA Director, point to findings that suggest that stigma-related bias among clinicians is a contributing factor to a treatment-averse mindset and to suboptimal clinical care, including the failure to implement proven methods of treatment. When a person with a mental illness or substance abuse disorder continues to experience stigma, they may begin to internalize it. This “self-stigma” often leads to poor self-esteem, feelings of lower self-worth, and can become an ongoing source of distress that may exacerbate symptoms and create barriers to successful treatment.

Reducing the stigma that is often associated with these conditions will help to alleviate the psychological burden it places on the affected individuals, breaking down the barriers to receiving effective healthcare. The authors highlight numerous studies showing that using scientifically accurate language and terms that centralize the experience of patients with mental illness and substance abuse disorders is one of the primary components to reducing stigma. They recommend that a shift in language is of critical importance for mobilizing resources toward mental health and addiction services and reducing the prejudices that prevent people from seeking help or receiving the quality of services they need. While the quest to eliminate the stigma and prejudice associated with mental illness and addiction, the authors contend that changing the language we use to describe these conditions can make a significant and immediate difference for the people experiencing them.

 

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