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National Institutes of Health (NIH) Research Updates – December 2020

The National Institutes of Health (NIH) is our nation’s medical research agency and strives to make 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 ground-breaking NIH research.

Recent NIH Research

A Sweet Treatment for Diabetes

Diabetes is a disease characterized by having an excess of glucose, a form of sugar, in the bloodstream.  While it has been well established that sugars play a pathogenic role in diabetes, a recent discovery by IRP researchers demonstrated that a particular form of sugar, D-mannose, actually protected diabetes-prone mice from developing type 1 diabetes.

Each November, Diabetes Awareness Month recognizes the millions of Americans living with type 1 diabetes or type 2 ‘adult onset’ diabetes. Type 1 diabetes is an autoimmune disorder in which the body’s own immune system attacks the insulin-producing beta cells in the pancreas. The hormone insulin is necessary for cells to convert the sugars in the food we eat into energy. Without insulin, sugar will build up in the bloodstream, causing inflammation and organ damage. Currently there is no cure for type 1 diabetes, and people with the condition must inject or infuse insulin on a daily basis to maintain healthy levels of the hormone.

One of the most common problems resulting from both type 1 and type 2 diabetes is an increased risk of infection, due in part to a weakening of the immune system.  In a prior study led by Dr. Wanjun Chen, scientists discovered that feeding diabetes-prone mice D-mannose, a sugar commonly found in certain fruits and vegetables, prevented the development of type 1 diabetes. They also found that D-mannose increased the generation of regulatory T (Treg) cells, a type of immune system cell that is vital to suppressing autoimmune inflammation, a leading cause of type 1 diabetes.

The finding from their study completely defied their expectations. While the glucose had no effect, an increased number of the control cells treated with D-mannose developed into regulatory T cells. Since an overactive immune response, resulting in the destruction of insulin-secreting cells is one of the primary causes leading to type 1 diabetes, this discovery suggests that D-mannose could actually be protective against the disease. Due to the specific mechanism by which D-mannose affects regulatory T cells, using the sugar to stave off type 1 diabetes is unlikely to suppress the immune system in the manner that Dr. Chen’s team thought glucose might.

The researchers originally selected D-mannose due to it’s similarity to glucose in both size and molecular weight, but having a different molecular structure.  It turned out that D-mannose is an important sugar that is involved in a variety of chemical reactions within the body. Like glucose, it can also be found in the bloodstream, though at much lower levels.

Although the mechanism leading to its protective qualities is not well understood, researchers theorize that D-mannose prevents bacteria from sticking to the walls of the urinary tract, thereby allowing them to be flushed out of the body. To gain a better understanding of this process, Dr. Chen and his colleagues decided to give the sugar to a variety of mice that typically develop diabetes by 12 weeks of age. While 90 percent of the mice that drank normal water developed type 1 diabetes by the age of 12 weeks, most of the animals that drank water sweetened with D-mannose remained healthy even at 23 weeks of age. While D-mannose did not reverse diabetes in mice that had already developed the condition, it did contribute to lowering their blood sugar.

“This was also surprising because the d-mannose not only prevented diabetes, but it also actually can stabilize blood sugar,” says Dr. Chen. “While the diabetic mice weren’t cured, their blood sugar stopped rising.”

Since the publication of these original experiments in Nature Medicine in 2017, Dr. Chen’s group has shown that D-mannose can play a role in suppressing obesity, which is a significant factor in controlling type 2 diabetes. The researchers hypothesize that D-mannose may help reduce inflammation, thereby preventing fat cells from expanding and contributing to weight gain. It is also possible that D-mannose helps correct an imbalance of the bacteria in the digestive tract, known as the gut microbiome, that is observed in people with obesity. This imbalance can lead to problems with the manner in which fat cells process and store nutrients. Future studies are required to further determine the relationships between the immune system, the gut microbiome, and obesity.

Scientists Douse Fat Burning to Combat Cancer

Fat provides more than twice as much energy as sugar and other carbohydrates, fueling not only healthy cells but also cancerous ones. A new IRP study, led by Dr. Paul Hwang, suggests that reducing the body’s ability to burn fat molecules for energy could slow the formation of tumors, potentially extending the lives of individuals with strong genetic predispositions to cancer.

One of the most commonly mutated genes in cancer cells is the TP53 gene, which produces a protein called p53 that assists the repair of damaged DNA and prevents runaway cellular division. In some rare cases, individuals are born with a TP53 mutation that affects all of their cells, leading to a condition called Li-Fraumeni syndrome (LFS) that dramatically increases their risk of developing numerous types of cancer early in life. Therefore, doctors who treat people with LFS screen them frequently for cancer so tumors can be dealt with as soon as they appear.

In the recent study, Dr. Hwang’s team focused on the process by which mitochondria produce energy from fat molecules, known as fatty acid oxidation. In a set of mice with mutated Trp53 genes, the scientists also knocked out the gene for a protein called myoglobin that helps transport oxygen in cells, an important step for fatty acid oxidation (hence the ‘ox’ in ‘oxidation’). Compared to mice with normal Trp53 genes, mice with mutated Trp53 genes had elevated fatty acid oxidation in their cancer-prone T cells. The mice with mutated Trp53 and myoglobin genes had lower levels of fatty acid oxidation than animals that only had a Trp53 mutation. Eliminating the myoglobin gene in mice with a Trp53 mutation delayed the development of lymphoma, thereby increasing their lifespan by approximately 40 percent. The majority of the mice still eventually developed lethal lymphoma.

Their research also revealed that mice with mutated Trp53 genes had more activity in a signaling pathway that is important for cell growth and which tumors often use to fuel their expansion. Elimination of the myoglobin gene significantly slowed this escalated growth system, providing a potential explanation as to why a decrease in fatty acid oxidation might delay the development of cancer.

“When you mildly inhibit mitochondrial function or fatty acid oxidation, you initiate a sort of cell braking system,” Dr. Hwang says. “If we can use that approach to delay cancer, that would be a great thing, especially because we could use drugs that are already available.”

The results of the study could inform changes in the treatment for patients with LFS, as well as other groups with a high risk for certain cancers.  Researchers at the National Cancer Institute (NCI) plan to evaluate whether current medications, such as metformin, might help delay the development of cancer in LFS patients, due to it’s ability to reduce mitochondrial activity.  Additional studies will be needed to determine if using a drug to specifically decrease fatty acid oxidation provides benefits that outweigh the potential side effects.

Study of “exceptional responders” yields clues to cancer and potential treatments 

A recent genomic study conducted by researchers at the National Cancer Institute (NCI) has uncovered molecular changes in patient tumors that provide hope for significant long-term responses to cancer therapy. In a comprehensive analysis of patients with cancer who had exceptional responses to therapy, the results demonstrate that genomic characterizations of cancer can uncover genetic alterations that may contribute to unexpected and long-lasting responses to treatment.

The retrospective study included detailed medical histories and tumor samples from 111 patients with various types of cancer who had received standard treatments, such as chemotherapy. The patients had been identified by NCI’s Exceptional Responders Initiative, a national project launched in 2014 to explore the feasibility of collecting and analyzing the data and biospecimens needed to better understand the biological basis of exceptional responses in cancer.

“The majority of patients in this study had metastatic cancers that are typically difficult to treat, yet some of the patient responses lasted for many years,” said Dr. Louis Staudt, director of NCI’s Center for Cancer Genomics, who co-led the study. “Researchers and the doctors who treat these patients have long been curious about the mechanisms underlying these rare responses to treatment. Using modern genomic tools, we can now start to solve these fascinating puzzles.”

In the context of this study, an exceptional responder is identified as someone who had a partial or complete response to a treatment that would be effective in less than 10% of similar patients. The duration of an exceptional response is one that lasts at least three times longer than the median response time.  Patient tissue samples were analyzed using several genomic approaches which include the analysis of DNA mutations, RNA expression levels, DNA copy number alterations, DNA methylation, and the analysis of the immune cells in the tumor microenvironment.

For 23 percent of the patients in the study, researchers were able to identify molecular features such as the co-occurrence of multiple rare genetic changes in the tumor genome or the infiltration of the tumor with certain types of immune cells that may have contributed to their exceptional response to treatment.  The mechanisms underlying exceptional responses in the study fell into several categories, including the body’s ability to repair DNA damage and the immune system’s response to tumors. Another category described rare combinations of genomic alterations that resulted in the death of tumor cells during treatment, known as synthetic lethality.

For example, the researchers identified mutations in the BRCA1 or BRCA2 genes in two patients with cancers that rarely involve alterations in these genes, which help repair DNA. The research suggests that in these patients, the mutations may have impaired the tumor’s ability to fix damaged DNA, thereby increasing the effectiveness of treatments such as platinum-based chemotherapy that harm DNA. “Our findings demonstrate the importance of testing patient tumors for alterations that may point to available treatments,” Dr. Staudt said. “There is a need for a shift towards molecular diagnosis of cancer that provides information that cannot be gleaned from looking at tumors through a microscope.”

In two of the patients treated with the DNA-damaging drug temozolomide, the researchers identified two DNA-repair pathways that needed to be simultaneously inactivated to achieve an exceptional response. This finding supports the development of drugs that block these DNA repair mechanisms, which might generally improve the responses of patients with cancer to temozolomide.

The study also focuses on the ability of the immune system to “kick in” and help eradicate tumors. In some patients in the study, increased levels of B lymphocytes, a type of immune cell, in tumors were associated with exceptional responses.

“As clinical researchers, we have a lot to learn from these patients, and they have a lot to teach us,” said Dr. Percy Ivy, of NCI’s Division of Cancer Treatment and Diagnosis, and co-leader of the research. “The knowledge gained from studying exceptional responders can help inform how we take care of patients in the future and will help move us closer to the goal of precision oncology.”

Additional research is required to further validate the results and hypotheses resulting from this study, but if confirmed, the findings could potentially provide leads for investigators trying to develop treatments that exploit the vulnerabilities of tumor cells like those found in some exceptional responders.

Envision color: Activity patterns in the brain are specific to the color you see 

Researchers at the National Eye Institute (NEI) have decoded brain maps of human color perception. The results from this study provide new insight into how color processing is organized in the brain, and how the brain recognizes and groups colors in the environment. These findings may also have implications for the development of novel machine-brain interfaces for visual prosthetics.

“This is one of the first studies to determine what color a person is seeing based on direct measurements of brain activity,” said Dr. Bevil Conway, chief of NEI’s Unit on Sensation, Cognition and Action, who led the study. “The approach lets us get at fundamental questions of how we perceive, categorize, and understand color.”

The brain processes the perception of color through the use of light signals that are detected by three types of retinal cone photoreceptors over a range of wavelengths. To characterize this process, Isabelle Rosenthal, Katherine Hermann, and Shridhar Singh, post-baccalaureate fellows in Conway’s lab and co-first authors on the study, used magnetoencephalography or “MEG,” a 50-year-old technology that noninvasively records the tiny magnetic fields that accompany brain activity. This technique allows for a direct measurement of brain cell activity using an array of sensors around the head. It can detect millisecond-by-millisecond changes that happen in the brain to enable vision.

As part of the study, a volunteer group was asked to view specially designed color images and report what they saw.  A spiral stimulus shape was used to present the color images, which is known to produce a strong brain response.  The researchers worked with pink, blue, green, and orange hues so that they could activate the different classes of photoreceptors in similar ways. These colors were presented at light and dark luminance levels.  The researchers found that study participants had unique patterns of brain activity for each color, which could allow for researchers to predict what color a volunteer was looking at through a color processing map of the brain.

“The point of the exercise wasn’t merely to read the minds of volunteers,” Conway said. “People have been wondering about the organization of colors for thousands of years. The physical basis for color—the rainbow—is a continuous gradient of hues. But people don’t see it that way. They carve the rainbow into categories and arrange the colors as a wheel. We were interested in understanding how the brain makes this happen, how hue interacts with brightness, such as to turn yellow into brown.”

While the study provided a multitude of insights into the process in which brain organizes and categorizes color, the goal is to hopefully utilize this information to uncover how the brain converts sense date into perceptions, thoughts and actions.

NIH researchers identify gene in mice that controls food cravings, desire to exercise 

A research team from the National Institute of Health (NIH) have discovered a gene in mice that controls the craving for fatty and sugary foods and the desire to exercise. The gene, Prkar2a, is highly expressed in a tiny region of the brain called the habenula, which is involved in responses to pain, stress, anxiety, sleep and reward. The findings could inform future research to prevent obesity and its accompanying risks for cardiovascular disease and diabetes. The study was conducted by Dr. Edra London, staff scientist in the section on endocrinology and genetics at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and colleagues.

Prkar2a contains the information needed to make two molecular subunit components of the enzyme protein kinase A. Enzymes speed up chemical reactions, either helping to combine smaller molecules into larger molecules, or to break down larger molecules into smaller ones. Protein kinase A is the central enzyme that speeds reactions inside cells in many species. In a previous study, the NICHD team found that despite being fed a high fat diet, mice lacking functioning copies of Prkar2a were less likely to become obese than wild type mice with normally functioning Prkar2a.

The scientists determined that Prkar2a-negative mice ate less high-fat food than their counterparts, not only when given unlimited access to the food, but also after a period of fasting. Similarly, the Prkar2a negative mice also drank less of a sugar solution than the wild type mice. The Prkar2a-negative mice were also more inclined to exercise, running 2-3 times longer than wild type mice on a treadmill. Female Prkar2a-negative mice were less inclined to consume high fat foods than Prkar2-negative males, while Prkar2-negative males showed less preference for the sugar solution than Prkar2-negative females.

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