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

Posted on NIH. 3 June, 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

Gene Editing Reveals Potential Cancer Treatment Target

IRP Scientists Investigate Wide-Ranging Effects of Endometrial Cancer Mutation

The effects of various types of cancer are widely variable even though they may originate from the same organ in the body.  One primary example is that of endometrial cancer.  The disease first manifests itself in the lining of a woman’s uterus, which is often asymptomatic in its early stages.  A rare form called uterine serous carcinoma can spread quickly throughout the body prior to detection and diagnosis.  A further cause of concern is its resistance to standard therapeutic cancer treatments such as radiation and chemotherapy.

Uterine serous carcinoma is present in about 5% of all cases and is often not the primary target of research surrounding uterine cancer. Dr. Daphne Bell, a senior investigator in the Intramural Research Program, is one of the few researchers focused on studying the disease. In a new study, she and IRP staff scientist Dr. Mary Ellen Urick, used the CRISPR DNA editing technique to investigate how altering a gene that is frequently mutated in serous endometrial cancer changes the production of thousands of cellular proteins.

CRISPR editing allows a researcher to precisely manipulate a gene of interest by adding or removing a specific mutation in that gene.  This novel technique provides a rapid and highly accurate tool to study the cellular effects of mutations.

The IRP team of researchers specifically focused on the gene FBXW7, which they had previously found to be mutated in nearly a third of serous endometrial cancers. Two groups of parental cells grown from two different serous endometrial tumors that did not have FBXW7 mutations were inserted into each cell using CRISPR editing. Six different varieties of serous endometrial cancer cells with abnormal FXXW7 genes were created by inserting one of three different FBXW7 mutations into each cell.  Protein levels from CRISPR edited cells were compared and analyzed against those found in non-mutated parental cells.

Their research identified hundreds of proteins that were present in significantly larger or smaller amounts in the CRISPR-edited cells as compared to the non-edited parental cells. Notably, the PADI2 protein was more than twice as abundant in all six sets of cells with FBXW7 mutations compared to the non-mutated parental cells.

While past studies have demonstrated that PADI2 levels are elevated in many other forms of cancer, Dr. Bell and Dr. Urick are the first researchers to correlate an increase in PADI2 production to serous endometrial cancer and FBXW7 mutations.

Preclinical studies have shown that inhibiting or reducing PADI2 levels slows the growth of several types of cancer and makes breast cancer cells more susceptible to chemotherapy, making the protein a potentially viable target in the treatment of serous endometrial cancer. Through their innovative research using CRISPR editing, IRP researchers have identified a potential treatment target for serous endometrial cancer.

Repurposed drug helps obese mice lose weight, improve metabolic function

Disulfiram is a medication which has been in use for over 50 years in the treatment of alcoholism. The drug works by inhibiting the processing of alcohol in the body, with very few side effects. In an international study led by researchers at the National Institute on Aging (NIA), disulfiram was shown to have consistently normalized body weight and reversed metabolic damage in obese middle-aged mice. Dr. Michel Bernier and Dr. Rafael de Cabo from the NIA first became interested in disulfiram after reading about the benefits this class of drug has shown in treating type 2 diabetes in rats, coupled with the growing interest in repurposing drugs that may also improve healthy aging.

The scientific team at NIA studied groups of 9-month-old lab mice who had been fed a high-fat diet for 12 weeks. The diet resulted in the mice becoming overweight in addition to showing signs of pre-diabetic metabolic problems, such as insulin resistance and elevated fasting blood sugar levels. The scientists divided these mice into four groups to be fed four different diets for an additional 12 weeks: a standard diet alone, a high-fat diet alone, a high-fat diet with a low amount of disulfiram, or a high-fat diet with a higher amount of disulfiram. The mice who stayed on the high-fat diet alone continued to gain weight and exhibit metabolic issues. Mice who were switched back over to a standard diet alone gradually saw their body weight, fat composition and blood sugar levels return to normal.

The mice in the remaining two groups, with either a low or high dose of disulfiram added to their high fat diet, showed a significant decrease in their weight and related metabolic damage. Mice on the high disulfiram dose lost up to nearly 40% of their body weight within four weeks, effectively normalizing their weight to that of obese mice who were switched back to standard diet. Mice in either disulfiram dose diet group became leaner and showed significant improvement in blood glucose levels on par with the mice who were returned to standard diet. Disulfiram treatment also appeared to protect the pancreas and liver from damage caused by pre-diabetic type metabolic changes and fat build up that is usually caused by eating a high-fat diet.

The positive results demonstrated during the study are largely due to disulfiram’s anti-inflammatory properties, which helped the mice avoid imbalances in fasting glucose and protected them from the damage of fatty diet and weight gain while improving their metabolic health. None of the groups of obese mice were subjected to any form of exercise, nor did they demonstrate noticeable behavioral changes or negative side effect from the drug during the experiment. Based on the evidence they observed, the researchers believe the beneficial results of disulfiram stem solely from the drug.  While disulfiram may have potential to help control morbid obesity based upon initial findings from the animal studies, further investigation of the drug is required to assess its efficacy for weight management in humans.

Tradition of Vaccine Breakthroughs (IRP Vaccine Research Stretches Back to the NIH’s Birth)

The discovery of vaccines in the prevention of infectious disease has been one of the most important medical advances worldwide.  Its history dates back over 200 years with the first vaccine introduced by British physician Edward Jenner, who in 1796 used the cowpox virus to protect against smallpox disease in humans. 

From its humble beginnings in a one room laboratory within the Marine Hospital on Staten Island, NY through its evolution over the course of its history more than 100 years ago, the Intramural Research Program has played an integral role in the development of approximately half of all FDA-approved vaccines currently in use.

Following a diphtheria outbreak in St. Louis, MO, the Biologics Control Act of 1902 granted responsibility for regulating the safety and efficacy of vaccines to the Hygienic Laboratory, which was the precursor agency to the National Institute of Health.  In 1972, the FDA assumed responsibility for the oversight of commercial vaccine production.

The smallpox vaccine was the first to be licensed by the Hygienic Laboratory in 1903.  NIH scientists, Vernon Fuller and Robert Kolb continued research on the disease over the next two decades, including the standardization of a vaccine potency test in 1968.  Through a global vaccination program, smallpox was eradicated by 1980.

Rocky Mountain spotted fever is a tick-borne illness which was usually fatal.  In the 1920’s, NIH scientists Roscoe Spencer and Ralph Parker created a vaccine for the illness by using ground up ticks mixed with phenol.  By the 1940’s, a half a million people in the Rocky Mountain region had been vaccinated against this disease.

NIH researcher, Sara Branham dedicated most of her career to the research and treatment of meningitis, an inflammation of the membranes surrounding the brain resulting from infection.  Dr. Branham along with technician Robert Forkish are credited with the discovery and characterization of Neisseria meningitidis, a common causative agent of the disease.   Her pioneering work on the disease ultimately led to the development of a vaccine for meningitis in the 1970’s.

NIH scientist Herald Cox developed the first methodology leading to the ability to mass produce vaccines during World War II.  The growth of sufficient amounts of the organism was difficult to impossible as it was only known to be present in lice.  Dr. Cox experimented with the inoculation of egg yolk sacs with rickettsia bacteria for the production of larger quantities of the organism leading to the development and mass production of vaccines for typhus, Q fever and Rocky Mountain spotted fever.

Rubella, also known as German measles, most commonly affects children and caused by the rubella virus.  In the mid 1960’s, the disease reached epidemic proportions, with nearly 20,000 infants born with congenital rubella syndrome due to the disease as reported by the Center for Disease Control (CDC). NIH’s Harry M. Meyer Jr. and Paul D. Parkman were among the first to isolate the virus that causes rubella in tissue culture.  By 1967 a live attenuated virus vaccine for rubella was licensed.

With over a million cases per year worldwide, hepatitis A is one of the most widespread of the viral hepatitis infections. In 1973, NIH researchers Robert Purcell and Albert Kapikain were the first to discover and characterize the hepatitis A virus using electron microscopy.  These initial studies led to the development of assays for the measurement of the viruses’ antigen and antibody, enabling the scientists to establish multiple previously unrecognized forms of viral hepatitis such as hepatitis strains B through E. With the assistance of FDA’s Stephen Feinstone and other collaborators, the team went on to develop the first vaccine for hepatitis A.

Bacteriologist Dr. Margaret Pittman joined the NIH in 1936.  Her research which was primarily focused on typhoid, cholera and pertussis (whooping cough) help lead to the development of vaccines for these diseases.  Due to the risk factors associated with using live infectious organisms for the production of vaccines, Pittman established potency and safety guidelines for vaccines as well as conceptual work surrounding the use of attenuated virus for the production of vaccines thereby vastly improving the safety of vaccinations.

The human papillomavirus, or HPV is the most commonly sexually transmitted virus and can lead to several types of cancer. During their 20 years of research within the IRP, Douglas Lowy and John T. Schiller found a way to produce virus-like particles (VLPs) that can inhibit HPV from infecting cells. This important discovery led to the first commercially available vaccine against HPV-associated cancer.

Since the onset of Covid-19 pandemic, a large majority of the research at the NIH has been focused on supporting the efforts surrounding the testing, treatment, development of a vaccine and ultimately a cure for this widespread disease.  Throughout the history of the NIH, researchers have been on the front lines of the fight against communicable diseases. Millions of lives worldwide have been saved from vaccine preventable illnesses due to the efforts of these dedicated researchers.

 

About Jason Blaine

Jason Blaine Jason Blaine is the Managing Director of Astrix Technology Group’s Federal Division and is a recruiting expert in the Scientific field. He joined Astrix in 2011 and has been responsible for the startup and success of the division by growing it from its infancy and into an emerging leader in the NIH contracting arena. Mr. Blaine helps NIH’s Investigators: 1) navigate the process of recruitment and retention of highly qualified candidates, 2) navigate the contracting process at NIH and 3) navigate the immigration process of hiring scientific personnel who require visa sponsorship. Mr. Blaine brings to the role over 15 years of experience in contracting personnel with NIH specifically in the scientific, clinical research, clinical, professional, and administrative fields.

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