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National Institutes of Health (NIH) Research Updates

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

Statins May Help Protect Hearing of Cancer Patients Undergoing Chemotherapy

Cisplatin is an anti-cancer, platinum-based chemotherapy drug that is used to treat a variety of solid tumors in both children and adults. Unfortunately, cisplatin has significant side effects which can include permanently inducing hearing loss in patients by destroying sensory cells of the inner ear. Scientists studying these sensory cells have known that they respond to harmful conditions (e.g., toxins, loud noises, etc.) by increasing production of protective molecules called heat shock proteins. Interestingly, statin medications have also been found to boost levels of heat shock proteins in cells, prompting IRP researchers to hypothesize that statins might preserve hearing in cancer patients undergoing cisplatin therapy.

In order to test their hypothesis, IRP lead investigator Lisa Cunningham, Ph.D. and her team administered two different hearing tests to mice both before and after prolonged cisplatin treatment. Dr. Cunningham’s team found evidence that a type of statin medication (lovastatin), originally designed to lower cholesterol, was in fact protective for hearing loss caused by cisplatin in the mice. Some of the mice given the prolonged cisplatin treatment were also given lovastatin both before and during the cisplatin treatment period. The researchers found that, as expected, cisplatin worsened the animals’ hearing as measured by both tests, while mice given a placebo or just lovastatin did not experience hearing loss. The mice given both cisplatin and lovastatin had far less hearing loss than those given just the cisplatin, however.

Interestingly, the researchers discovered that lovastatin use reduced the number of sensory hair cells that cisplatin treatment destroyed, and it was particularly protective of the hearing range that is typically most impaired by cisplatin treatment (high and medium-pitched sounds). It is noteworthy that high and medium-pitched sounds are often what allow humans to distinguish between different words and thus critical for human communication.

Finally, the researchers noted that lovastatin did not prevent harmful buildup of platinum in the inner ear that often results from cisplatin treatment. However, the lovastatin use did boost production of two potentially protective heat shock proteins. That said, the researchers did not determine in this study whether the increase in heat shock proteins was the mechanism by which lovastatin successfully protected the hair cells.

Future studies will explore this mechanism, and clinical trials are being planned to test whether statins reduce hearing loss in cancer patients undergoing cisplatin therapy. The hope is that, if these studies show statins are effective in reducing hearing loss in humans using cisplatin, statin medications can be utilized in clinical settings to help cancer patients.

Researchers Identify Type of Immune Cells Causing Damage in Lupus

Lupus is an autoimmune disease in which a person’s immune system attacks the body’s own cells in the same way it would go after harmful invaders like bacteria or viruses. Lupus patients typically experience unpleasant symptoms like pain, fatigue and rashes, while also being highly prone to cardiovascular disease (CVD). As with all autoimmune diseases, treatments for lupus involve immune system suppression. While these treatments reduce symptoms, they also leave patients vulnerable to other diseases that our immune system normally protects us against.

Past research on the immune systems of lupus sufferers revealed that neutrophils, the most abundant white blood cell in our bodies and typically one of the first to be activated in an immune response, are the primary cause of tissue damage for this disease. IRP researchers lead by senior investigator Mariana Kaplan, M.D., subsequently discovered that a specific type of neutrophils (low-density granulocytes or LDGs) were the primary culprits.

In a new study, Dr. Kaplan and her team sought to further narrow down the type of neutrophils that cause tissue damage in lupus using state-of-the-art laboratory technology and procedures. Utilizing these techniques, the IRP team was able to identify a small subset of LDGs with genes that where much more active. Additional experiments revealed that the LDGs with more active genes were missing a molecule called CD10 on their surfaces, suggesting that they were ‘immature’, since ‘mature’ neutrophils in later stages of their life always contain CD10. The team also noted that mature neutrophils are much more effective at immune functions in general than the immature LDGs.

A clear picture began to emerge when the IRP team examined a separate set of lupus patients and found that higher numbers of CD10-positive, mature LDGs in their blood were associated with greater levels of lupus-induced tissue damage. At the same time, the team found no correlation between immature LDGs and tissue damage, suggesting it was the mature LDGs that were involved in creating lupus symptoms, including the number one cause of death in lupus patients (CVD).

Moving forward, the IRP team is hopeful that this information will allow scientists to identify drugs that target specific neutrophil subsets to reduce incidences of CVD in lupus patients, as well as those with other autoimmune diseases where LDGs have been identified and CVD is prevalent. The team’s findings could also provide useful clinical biomarkers that would allow clinicians to identify and aggressively treat patients with higher numbers of mature LDGs. Finally, discovering the specific processes that make the mature LDGs harmful could allow the development of therapies that return these cells to more normal function.

Researchers Discover a Genetic Mutation in Mice that Improves Cognitive Flexibility.

NIH researchers led by Dax Hoffman, Ph.D., chief of the Section on Neurophysiology at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), have discovered in mice experiments what they believe to be the first known genetic mutation that improves cognitive ability to adapt to changing situations, otherwise known as cognitive flexibility. The KCND2 gene creates a protein that controls the electrical signals traveling along neurons by regulating potassium channels. These electrical signals are responsible for stimulating the chemical messengers that travel across the synapses between neurons.

Dr. Hoffman’s team found that modifying a single base pair in the KCND2 gene with an enzyme enhanced the ability of the KCND2 protein to dampen nerve impulses. The team observed that mice with this mutation performed had better cognitive flexibility than mice without the mutation. Specifically, the mice with the mutation were able to find and swim to a slightly submerged platform that had been moved to a new location much faster than the cohort without the mutation.

The researchers plan to investigate whether the mutation effects the neural networks in the mice’s brains, and hope that study of this gene and protein will lead to better insights on cognitive flexibility in humans. In addition, the scientists also hope the understandings gained in this research will help improve understanding of epilepsy, schizophrenia, Fragile X syndrome, and autism spectrum disorder, all of which are associated with other mutations in KCND2.

NIH Researchers Discover Gene for Rare Disease Causing Overgrowth of Bone Tissue

Melorheostosis is a rare group of conditions affecting about 1 in a million people that involves an often painful and disfiguring overgrowth of bone tissue. While the causes for this disease have long been unknown, a group of researchers at the NIH in 2018 found a gene (MAP2K1) that appeared to play a key role by taking a biopsy of the affected bone directly and comparing it to unaffected bone. In that study, mutations in the gene MAP2K1 accounted for eight cases of a type of melorheostosis known as “dripping candle wax bone disease” among 15 patients.

More recently, NIH researchers scanned the exome of patients suffering from melorheostosis and found mutations in the SMAD3 gene, which is part of a pathway that regulates skeletal development before and after birth, in the affected bone. As the SMAD3 gene is involved in maturation of bone-forming cells, its metabolic pathway is distinct from the MAPK1 gene. In four melorheostosis patients in the study, the researchers found SMAD3 mutations but no MAP2K1 mutations.

Interestingly, instead of being inherited from parents, the mutations occurred during the patient’s lifetime and are not present in all body cells. The NIH researchers are currently working on an animal model to test potential treatments for the condition with a mutant version of SMAD3.