Posted on Lab Informatics. 3 February, 2020
As part of the U.S. Department of Health and Human Services, the National Institutes of Health (NIH) is our nation’s medical research agency and strives to make important 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. The NIH also provides biomedical research funding for non-NIH research facilities via its Extramural Research Program, investing nearly $39.2 billion in external medical research in 2019.
In a study conducted by the Nature Index in 2019, the NIH ranked #2 in the world in terms of published scientific papers, behind only Harvard University in Boston. In this blog, we will highlight recent ground-breaking research that has been conducted through the NIH IRP, while also providing links to upcoming NIH events designed to keep researchers abreast of the latest discoveries.
Epigenetic DNA Methylation Changes Discovered in Infants Born to Mothers Who Smoked During Pregnancy.
Babies born to mothers who smoked during their pregnancy often have impaired lung function at birth, typically weigh less than babies born to non-smoking mothers, and have a higher risk of respiratory illness during childhood. A recent study led by IRP researchers found ‘epigenetic’ methylation changes to certain genes (which can alter their behavior) in DNA were significantly different in smoking mothers compared to their babies.
Using a technique called pathway analysis, researchers were able determine that several of the genes in infants born to maternal smokers that were affected were involved in the production of inflammatory cytokines. The researchers also determined that these genes helped determine the way our bodies process certain chemicals – those found in tobacco smoke (e.g., nicotine), some pharmaceuticals, etc. These findings suggest that prenatal exposure to cigarette smoke may have unique and long-lasting effects on bodily functions in children.
Researchers involved in this study are planning follow-up studies with larger numbers of adults and newborns that may provide further insights. Other future studies will likely focus on determining the specific biological processes that may be altered in infants born to maternal smokers. In addition, future research could focus on identifying the specific biological mechanisms by which a mother’s smoking changes DNA methylation in a developing fetus, potentially leading to even deeper biological insights.
New Treatment Suppresses Breast Cancer Metastasis in Mice
While the process by which cancerous tumors spread into other body tissues (metastasis) is not fully understood, there is evidence that tumors can modify the extracellular matrix (three-dimensional network of molecules that surround cells in our organs) around themselves and also in other distant parts of the body to create a more welcoming environment for cancer cells. This fact prompted scientists lead by IRP senior investigator William Stetler-Stevenson, M.D., Ph.D. to investigate molecules our bodies use to regulate changes to the extracellular matrix for potential cancer therapies.
A recent study which flowed from these investigations found compelling evidence that a molecule naturally produced in the body (TIMP-2) can suppress the growth and spread of triple-negative breast cancer (TNBC), a particularly lethal form of the disease, through direct effects on the tumor, and also by altering the extracellular matrix in surrounding tissue in ways that makes the tissue less hospitable to the cancer cells. IRP researchers found that giving TIMP-2 daily for 3 weeks both inhibited the tumor growth in the site it was implanted, and also reduced the number of cancer cells in the animal’s lungs by 90% compared to untreated mice. Additionally, the TIMP-2 application did not produce any measurable side effects.
The IRP researchers plan to investigate TIMP-2 in other animal cancers, refine the treatment delivery method, and experiment with modifications in the TIMP-2 molecule itself to increase efficacy. Going forward, the team is hopeful that TIMP-2 could be utilized in concert with classical chemotherapies, or other therapies that promote tumor cell destruction, that do not facilitate normalization of the extracellular matrix.
Protein Linked to Neurodegenerative Diseases Found to Bypass Mitochondrial Defenses to Damage Neurons.
In Parkinson’s disease, neurons produce abnormally large amounts of a protein called alpha-synuclein. As this substance builds up inside the neurons, it moves inside the mitochondria (the energy producing factories inside our cells) and interferes with the energy production that the cells need to survive, ultimately causing neuron death. The mechanism by which the alpha-synuclein enters the mitochondria has eluded scientists, however, as mitochondria have built-in defenses designed to make sure that unwanted substances do not get inside and interfere with their important function.
A clue to this mystery emerged in 2015 when a French pharmaceutical company published research showing that a drug called olesoxime effectively protected neurons from the buildup of alpha-synuclein. Scientists at the company also found that olesoxime binds to a protein on the outer surface of the mitochondria (VDAC) which allows certain molecules to move in and out of mitochondria.
Given that her lab had found earlier that same year that alpha-synuclein interacts with VDAC, an IRP staff scientist named Tatiana Rostovtseva, Ph.D. set out to determine if VDAC is involved in olesoxime’s ability to protect mitochondria from alpha-synuclein with one of the postdoctoral fellows in her lab. In order to determine if VDAC was necessary for alpha-synuclein to gain entry into mitochondria, the scientists significantly reduced the amount of VDAC in cells commonly used to study neuronal function. Without VDAC, they found that alpha-synuclein did not accumulate inside the mitochondria, effectively demonstrating that VDAC was the channel through which alpha-synuclein enters mitochondria.
Additional research provided confirming evidence that olesoxime protects mitochondria from alpha-synuclein by hindering its ability to pass through VDAC. Given that VDAC is the main mitochondrial site affected in many neurodegenerative diseases, Rostovtseva and her team feel that future research should consider VDAC as a target for other drugs and diseases.
Rare Disease Research Could Improve Therapy for Multiple Autoimmune Diseases
Co-discovered in 2014 by IRP researchers led by Daniel Kastner, M.D., Ph.D., a rare illness called deficiency of adenosine deaminase 2 (DADA2) has been diagnosed in less than 200 patients worldwide. This affliction is caused by mutations in both copies of a person’s ADA2 gene, which produces the enzyme adenosine deaminase 2. DADA2 is essentially an autoimmune condition where the immune system attacks blood vessels, creating inflammation and damage. Severe cases of DADA2 result in strokes and bleeding in the brain.
IRP Senior Investigator Peter Grayson, M.D., M.Sc. began studying DADA2 after watching a YouTube video about a woman and her two children who had another form of vasculitis known as polyarteritis nodosa (PAN). Dr. Grayson found the video intriguing because PAN does not run in families, while DADA2 does. Suspecting that the family had DADA2, Dr. Grayson brought them into the NIH Clinical Center for genetic testing and confirmed they had DADA2.
With curiosity peaked, Dr. Grayson’s team began testing blood and tissue samples from DADA2 patients. They discovered that patient’s blood contained significantly more neutrophils (immune system early responders) when symptoms were at their worst. In addition, the scientists discovered that toxic web-like structures called neutrophil extracellular traps (NETs) that are used to kill bacteria but can also cause tissue damage were present in inflamed tissue samples from DADA2 patients.
Another relevant discovery was that patients with DADA2 had significantly higher amounts of adenosine in their blood than healthy individuals, which was clearly due to the fact that they lacked the ADA2 enzyme that breaks it down. Additional experiments showed that the more adenosine that neutrophils were exposed to, the more NETs they produced, and that this affect could be reduced by adding ADA2 enzymes to the mix. The clear conclusion was that it was the deficiency of ADA2 enzymes in DADA2 patients that caused the overproduction of NETs. Interestingly, the researchers found that neutrophils in female patients produced significantly more NETs when exposed to adenosine than male patients, which may explain why autoimmune diseases are more common in women than men.
In addition, Dr. Grayson’s team found significant potential to treat people with DADA2 by altering the way immune cells respond to adenosine. The team found that adenosine caused much less NET formation by neutrophils when they were exposed to chemicals that blocked a specific adenosine receptor (A1). Also, the team found that macrophages (another immune system early responder) responded to NETs from DADA2 patients by secreting inflammatory cytokines, but that activating the A2 adenosine receptor on macrophages stopped NETs from causing the macrophages to produce inflammatory molecules. This research highlights potential treatments for patients with DADA2 and other autoimmune conditions with therapies that target the adenosine system.
The NIH sponsors a wide variety of talks, webinars and other events designed to help keep NIH researchers abreast of the latest and most important medical research in the United States and beyond. NIH institute-sponsored or related events held at or near the NIH’s Bethesda, Maryland, campus in the month of February can be found here.
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