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

Scientists identify small-molecule cocktail to improve stem cell use in research and disease treatments

Human pluripotent stem cells hold promise in the field of regenerative medicine due to their ability to propagate indefinitely and differentiate into specialized cell types such as heart, brain and kidney cells. Through genetic reprogramming, induced pluripotent stems cells (iPSCs) are created that bring these cells back into an embryonic-like pluripotent state, enabling the development of an unlimited source of any type of human cell required for research or therapeutic uses. However, iPSCs are sensitive to stress which can result in DNA damage or cell death.

A team of researchers at the National Center for Advancing Translational Sciences (NCATS) have developed a small molecule cocktail capable of protecting iPSCs from stress to maintain normal structure and function. Their findings indicate that the cocktail, called CEPT, could enhance the potential therapeutic uses of stem cells in treating diseases and conditions such as diabetes, Parkinson’s disease and spinal cord injury.

The research team, led by Dr. Ilyas Singeç, director of the Stem Cell Translation Laboratory  at NCATS, used high-throughput screening to test more than 15,000 FDA approved drugs and investigational small-molecule compounds to identify a unique combination that significantly improved stem cell viability and protects against stress during culture and cryopreservation. Among the 20 drugs and compounds that demonstrated the ability to inhibit the activity of ROCK, a type of kinase enzyme that is involved in stem cell stress, the team found that the compound Chroman 1 was more potent than the widely used compound Y‑27632 in improving cell survival.

“The small-molecule cocktail is safeguarding cells and making stem cell use more predictable and efficient. In preventing cellular stress and DNA damage that typically occur, we’re avoiding cell death and improving the quality of surviving cells,” said Dr. Singeç. “The cocktail will become a broadly used staple of the stem cell field and boost stem cell applications in both research and the clinic.”

To further improve cell survival, the researchers used NCATS’ matrix combination screening technology to identify potential synergies between Chroman 1 and other drugs and compounds. Matrix drug screening enables investigators to study the effects of drug combinations and determine possible mechanisms by which these drugs act. The researchers identified that Emricasan, an investigational drug, in combination with Chroman 1 increased stem cell viability.

According to Dr. Singeç, an important effort in stem cell biology is single-cell cloning, culturing one cell at a time in a tiny well of a cell culture plate. The process has critical applications in gene editing and establishing cell lines, which are derived from a single cell. In their initial screening work, the team tested the protective effects of drugs and compounds on 500 stem cells at a time in plate wells. To mimic the cell stress seen during single-cell cloning, the researchers developed a new assay to allow them to examine the effects of more than 7,500 compounds on only 10 cells at a time. This effort led to the identification of a third compound, trans-ISRIB, that enhanced cell survival, even when there were a few cells in each plate. Additional experiments revealed that a mixture of polyamines, in combination with Chroman 1, Emricasan and trans-ISRIB, provided the best conditions for single-cell cloning.

“Cells need to be cultured properly, and they have to be of good quality to go into patients,” said Dr. Joni Rutter, NCATS Acting Director. “By finding new ways to protect stem cells from damage, these results could eventually have wide-ranging implications for many different diseases, including cancer, Alzheimer’s disease and more.”

Additional studies confirmed that that CEPT improved the biobanking of stem cells during cryopreservation, which involves freezing the cells and typically is very stressful for them. Cryopreservation is critical to bringing stem cells to the clinic, but causes cell loss or damage during the thawing process. The team also found that CEPT treatment on cells that were differentiated into heart cells, motor neurons and other cell types improved viability and function. Dr. Singec indicated that their approach could improve safety and ensure that the next-generation stem cell lines are cultured at high quality before moving into the clinic. He also noted potential uses for the cocktail in tissue engineering and the biomanufacturing of various cell types for regenerative medicine and drug development.

A ray of hope for a rare and deadly skin cancer

Merkel cell carcinoma (MCC) is a rare, aggressive type of skin cancer that primarily effects the head and neck region. Sun exposure or a weakened immune system are contributing factors in the development of MCC. The survival rate when detected in the early stages of the disease is approximately five years with a median survival time of nine months for advanced stages of MCC.

This bleak outlook changed radically in 2017 with the FDA approval of a new immunotherapy drug called avelumab. This first-ever FDA approved treatment specifically for MCC was developed through a collaboration between IRP researchers and EMD Serono, Inc. and marketed as BAVENCIO^® .

“Avelumab changed the way we treat this cancer and it changed the prognosis of this cancer,” says IRP investigator Dr. Isaac Brownell, who co-led the preclinical research on avelumab at the NIH along with IRP senior investigators Dr. James Gulley, and Dr. Jeffrey Schlom.

Avelumab is a member of a class of immunotherapies known as ‘checkpoint inhibitors.’ The immune system is controlled by a protein on each immune cell called a ‘checkpoint’. Their role is to prevent an immune response from being so strong that it damages healthy cells. Many of the body’s normal cells are marked with a protein called programmed death-ligand 1 (PD-L1), which prevents immune cells from attacking healthy cells. However, certain forms of cancer, including MCC, also have PD-L1, thereby preventing the immune system’s T cells from launching an assault against them.

“The T cell may be specific to that tumor, may recognize that tumor, may be able to kill that tumor, but it’s prevented from doing so because the PD-L1 marker is present” Dr. Gulley explains. “Avelumab works like putting a bag over a stop sign — it hides the PD-L1 from the T cells, so they just go ahead and do their work.”

Dr. Gulley and Dr. Schlom began their work on avelumab in 2013 when a former IRP colleague became the chief medical officer at EMD Serono and invited Dr. Gulley to collaborate on a promising agent in their product pipeline.

The initial safety and efficacy trials of avelumab focused on treating people with a variety of cancers that the researchers believed would respond to immunotherapy. The combined research team conducted what the FDA calls a ‘seamless trial,’ which is intended to accelerate the development and approval of cancer treatments without compromising patient safety by condensing two or more phases into one adaptive design study. As a result, they were able to enroll more than 1,700 cancer patients in the study over a short period of time.

During the trial period, Dr. Brownell, a dermatologist at the NIH Clinical Center, approached Dr. Gulley for help designing a study specifically targeting MCC. This led to the idea to also test avelumab in 88 patients with an advanced form of the cancer who also had not responded to chemotherapy treatment. 33 percent of the patients had a reduction in tumor size following avelumab treatment, with many showing improvements for six months or longer. These effects were evident after only six weeks of treatment, with some of the patients treated in that 2013 trial still alive today.

While avelumab has greatly improved the prognosis for MCC, it is having a positive impact on other cancers as well. The FDA has already approved avelumab for treating two types of bladder cancer and renal cell carcinoma in combination with another drug.

Eating habits change only slightly after gestational diabetes diagnosis, NIH study suggests

Gestational diabetes is a condition that occurs due to high blood sugar levels during pregnancy. Approximately 10% of women in the US, who have not previously been diagnosed with diabetes prior to pregnancy, are affected by this condition. Pregnant women with gestational diabetes have a higher risk of maternal high blood pressure, larger babies, cesarean delivery, low blood sugar in newborns, and development of chronic diabetes later in life.

In a recent study led by Dr. Stefanie Hinkle, of the Epidemiology Branch at Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), researchers found that pregnant women made only modest dietary changes after being diagnosed with gestational diabetes. Nutritional recommendations for controlling gestational diabetes include a reduction in carbohydrate intake and to limit high-fat foods.

The team of researchers analyzed an existing set of data from the NICHD Fetal Growth Studies, which included surveys on diet and exercise from a diverse group of women at 12 hospital centers across the country. The analysis on diet included 1,371 women, of which 72 had gestational diabetes. The team also examined the exercise routines of 1,875 women, of which 84 had gestational diabetes.

In the current study, women with gestational diabetes limited their daily carbohydrate intake by 48 grams primarily by reducing their juice consumption by about 0.4 cups per day and reducing their added sugar consumption by about 3.2 teaspoons per day. Their consumption of cheese increased by 0.3 cups per day, however, their intake of artificially sweetened beverages increased by 0.2 cups per day. The women did not decrease their consumption of whole grains or whole fruit, nor did they compensate for their dietary changes by significantly increasing saturated fats. The team also observed that women with gestational diabetes maintained the same level of exercise into their third trimester, but noted an overall reduction in exercise during the third trimester in the group of women who did not have gestational diabetes.

“The improvements in diet that we observed were not equitable across all groups of women,” said Dr. Hinkle. “This research highlights the importance of creating individualized programs to ensure that all women with gestational diabetes are successful at modifying their diet and optimizing their health.”

According to the study authors, the findings show that healthcare providers still have many opportunities to help women manage gestational diabetes through dietary modifications and exercise. Future studies will focus on innovative approaches that are more effective in changing nutrition and exercise-related behaviors.

Male hormones regulate stomach inflammation in mice

In a new study published in Gastroenterology, a team of researchers from the National Institute of Environmental Health Sciences (NIEHS) determined that stomach inflammation is regulated differently in male and female mice after finding that androgens, male sex hormones, play a critical role in preventing inflammation in the stomach.

The research team made this discovery after removing the adrenal glands from mice of both sexes. Glucocorticoids, which are hormones produced by the adrenal glands, play an important role in regulating certain aspects of the immune system, such as inflammation. In this study, following the removal of the adrenal glands, the female mice developed inflammation of the stomach while the males did not. When androgens were also removed from the male mice, they exhibited the same stomach inflammation observed in the female mice.

“The fact that androgens are regulating inflammation is a novel idea,” said co-corresponding author Dr. John Cidlowski, deputy chief of the NIEHS Laboratory of Signal Transduction and head of the Molecular Endocrinology Group. “Along with glucocorticoids, androgens offer a new way to control immune function in humans.

Dr. Cidlowski indicated that while this study provides insight into how inflammation is being regulated in males, additional research is underway to understand the process in females. The scientist responsible for this phase of the research is co-corresponding author Dr. Jonathan Busada, assistant professor at West Virginia University School of Medicine, and prior postdoctoral fellow in Dr. Cidlowski’s group.

Whether inflammation is inside the stomach or elsewhere in the body, rates of chronic inflammatory and autoimmune diseases vary depending on sex, said Dr. Busada. Eight out of ten individuals with autoimmune diseases are women. His long-term goal is to determine the role of glucocorticoids and androgens in stomach cancer, which is induced by chronic inflammation.

The current research is focused on stomach glands called pits, which are embedded in the lining of the stomach. Dr. Busada said the study showed that glucocorticoids and androgens act like brake pedals on the immune system and are essential for regulating stomach inflammation. In his analogy, glucocorticoids are the primary brakes and androgens are the emergency brakes.

“Females only have one layer of protection, so if you remove glucocorticoids, they develop stomach inflammation and a pre-cancerous condition in the stomach called spasmolytic polypeptide-expressing metaplasia (SPEM),” said Dr. Busada. “Males have redundancy built in, so if something cuts the glucocorticoid brake line, it is okay, because the androgens can pick up the slack.”

The research team also offered a possible mechanism responsible for this phenomenon. In healthy stomach glands, the presence of glucocorticoids and androgens inhibit special immune cells called type 2 innate lymphoid cells (ILC2s). But in diseased stomach glands, these hormones are missing. As a result, ILC2s may act like a fire alarm, directing other immune cells called macrophages to promote inflammation and damage gastric glands leading to SPEM and ultimately cancer. Dr. Cidlowski concluded that since ILC2s are the only immune cells that contain androgen receptors, they could be a potential therapeutic target.

Enzyme therapy helps rebuild teeth

Periodontal disease is an infection of the gums, leading to the deterioration of the soft tissue and bone that supports the teeth. In its early stages, called gingivitis, the gums become inflamed and bleeding may occur.  As the condition advances into periodontitis, the resulting bone loss could cause teeth to loosen or fall out.

In a new study, IRP researchers identified a promising new strategy for treating periodontal disease to help the body regenerate a part of the tooth, called cementum, that is difficult to repair. Cementum surrounds the roots of our teeth and attaches them to our jawbone by anchoring them to the periodontal ligaments.

“The cementum around the tooth root is one of the tissues that has to be repaired to restore the tooth’s function after periodontal disease,” explains Dr. Martha Somerman, IRP senior investigator and the study’s senior author. “A lot of scientists have been focusing on promoting bone regrowth, but if you do that without considering the need for a healthy cementum, you will not restore proper function.”

Cementum that has been damaged doesn’t naturally regenerate very quickly and current approaches to restoring it have not proven to be effective. To address this issue, Dr. Somerman’s team investigated whether an enzyme naturally found in the human body called alkaline phosphatase (ALP) could help repair damaged cementum by boosting the process of mineralization responsible for building teeth and bone. Previous studies have shown that ALP transforms a chemical called pyrophosphate, which inhibits mineralization, into another molecule called phosphate, which promotes mineralization.

The IRP research team utilized a mouse model to study periodontal disease that lacks the gene for bone sialoprotein, a key protein responsible for building bone and cementum. The researchers began by giving five-day-old mice a ‘systemic’ therapy that quadrupled their blood’s level of tissue-nonspecific alkaline phosphatase (TNAP), a form of ALP found in bones. At two months of age, the mice that received the therapy produced cementum that was more than double the thickness of the cementum of their untreated counterparts. They also exhibited greater growth of the jawbone surrounding the cementum, resulting in teeth that were well-attached to the periodontal ligament comparable to the genetically normal mice.

“Bone sialoprotein is thought to be a critical molecule for mineralization,” Dr. Somerman explains, “so this is a perfect proof-of-principle model to examine whether you can regenerate cementum.”

Next, using five-week-old mice with the same genetic defect, Dr. Somerman’s team investigated the effects of delivering TNAP directly to the area where the degraded periodontal tissue was rather than raising TNAP levels in the entire body. The treated animals showed similar beneficial effects to the mice that had received the systemic TNAP-boosting therapy. The locally delivered TNAP treatment also promoted growth of the cementum and surrounding jawbone in genetically normal mice.

The research team also determined that ALP corrected mineralization deficiencies in cementum-producing cells, called cementoblasts, that had the same genetic defect as the mice. Treating those cells with a chemical that disrupts the transport of phosphate into cells diminished the ALP’s beneficial effects. This led the team to the conclusion that the TNAP treatment given to the mice promoted regeneration of the cementum and surrounding bone by increasing the amount of phosphate available for cementoblasts to use for the rebuilding process.

“We’re incredibly excited about this,” Dr. Somerman says. “Our studies showed that even in a normal mouse that doesn’t have a genetic defect, you can promote the formation of cementum. It is very rewarding to identify factors, such as TNAP, as promising therapies for individuals with periodontal disease.”

Since TNAP is FDA-approved for use in humans with genetic TNAP deficiencies, its adoption as a treatment for rebuilding the cementum and jawbone of people with severe periodontal disease could be accelerated. The ability to deliver TNAP directly into the damaged area would also likely have fewer side effects than introducing it throughout the body. The research team would like to focus their future studies on refining the TNAP treatment and moving those therapies into clinical trials.

Upcoming Events:

Gene-Targeted Therapies: Early Diagnosis and Equitable Delivery

Thursday, June 3, 2021, 12:00 pm to Thursday, June 17, 2021, 4:30 pm (registration required)

ASPIRE Day 2021 is a virtual workshop hosted by NCATS to showcase recent advances and promote collaborations in automated medicinal chemistry and biological annotations to enable efficient translation in preclinical discovery.

Thursday, June 3, 2021, 1:00 pm to Friday, June 4, 2021, 12:00 pm

NIH Summit on Anti-SARS-CoV-2 Antibodies for Treatment and Prevention of COVID-19: Lessons Learned and Remaining Questions

Tuesday, June 15, 2021, 11:00 am to 4:00 pm

The NIDCD Mouse Auditory Testing Core Facility’s role in identifying hearing loss

Thursday, June 17, 2021, 12:00 pm to 1:00 pm

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

Friday, June 18, 2021, 1:00 pm to 4:00 pm

NCI-CONNECT Survivorship Care in Neuro-Oncology Symposium

Monday, June 21, 2021, 1:00 pm to 5:00 pm

Future Research Leaders Conference

Tuesday, June 29, 2021 to Wednesday, June 30, 2021

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

Wednesday, August 25, 2021, 1:00 pm to 5:00 pm