Posted on NIH. 5 January, 2021
The National Institutes of Health (NIH) is our nation’s medical research agency. It’s 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.
As we begin the new year, many people are setting their sights on resolutions and goals for the coming year. Annual health goals often times include weight loss as a primary objective for those who are overweight or obese. For some this has become a reoccurring New Year’s resolution following prior unsuccessful attempts. A New IRP research study suggests that repeatedly losing and regaining weight is better for health than never losing weight at all and may significantly reduce a person’s risk of dying.
The majority of individuals who embark on a weight loss program may initially lose weight, however, recent studies have estimated that between 65 to 80 percent of those people have a tendency to gain some or all of it back within a few years. Other studies have also suggested that there may be health risks associated with ‘weight cycling’, repeatedly losing and gaining significant amounts of weight.
“There’s this idea in the scientific literature that weight cycling is bad,” says IRP senior investigator Dr. Sonja Berndt. “As a result, doctors often are not sure what to advise their patients, and the patients start to think, ‘Why should I even attempt to lose weight, since I’ll just gain it back again?’”
Some researchers, including Dr. Berndt, are skeptical of past studies that link weight cycling to an increased risk of dying. Many studies have not taken into account whether the participants’ weight loss was intentional or due to an illness. This is a significant methodological oversight in those studies due to the fact that many people who are ill and therefore more likely to die as a result of their illness, experience weight loss without trying to. Some past research has also failed to consider other factors associated with weight changes, such as a person’s starting weight and health-related behaviors including smoking.
To further understand the correlation of weight cycling on overall health, a team of IRP scientists led by Dr. Berndt analyzed data from over 100,000 men and 61,000 women to determine the relationship between the number of times a person has tried to lose weight and his or her odds of dying from any cause. Contrary to studies claiming that weight cycling is bad for health, the IRP research team found that the more times a person intentionally lost at least five pounds over a 20-year period, the less likely he or she was to die during the follow-up period, even if that person regained the lost weight. The study concluded that repeatedly losing and re-gaining weight was more beneficial than giving up after one or two attempts or, never attempting to lose weight at all.
“These people who are attempting weight loss many times are likely engaging in lifestyle changes that are beneficial for them,” Dr. Berndt explains. “Maybe they’re eating healthier foods or maybe they’re exercising more during each of these weight loss attempts, and over time those benefits accumulate because they have more time during which they are engaging in healthy behaviors. Even if they were not successful at losing weight, because they were engaging in these healthy behaviors, they saw a benefit.”
The IRP research team noted a similar relationship between attempted weight loss and a reduced risk of death regardless of the starting weight of the study participants. They also observed a trend suggesting that more weight loss attempts might decrease the risk of dying from cancer and cardiovascular disease in particular. In addition, among a subset of individuals who had never tried to lose weight, those who lost weight unintentionally were more likely to die than those who maintained their weight or gained weight, lending support to the theory that it is important for studies to differentiate between intentional versus unintentional weight loss that may have resulted from an underlying illness.
The study concluded that people who had lost 100 pounds or more in total over a period of 20 years were less likely to die if they had lost the weight over many smaller attempts versus having lost all of the weight in a few large efforts. This suggests that going to extreme measures to drop large amounts of weight all at once may not be the most effective strategy for healthful weight loss.
“The more you try, the better — that’s our take home message,” Dr. Berndt says. “If you’re overweight or obese, you shouldn’t think, ‘I tried once and I failed, so I’m not going to try again.’ It’s still good to try even if you fail.”
Researchers at the National Institutes of Health (NIH) have made a remarkable discovery surrounding the genetic mutation normally understood to cause Huntington’s disease and its association with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), two disorders of the nervous system.
This large, international project, which included a collaboration between the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), opens a potentially new avenue for the diagnosis and treatment of certain individuals with FTD or ALS.
Several neurological disorders, including Huntington’s disease, have been linked to “repeat expansions,” a type of mutation that results in abnormal repetition of certain DNA building blocks. Huntington’s disease occurs when a sequence of three DNA building blocks that make up the gene for a protein called huntingtin repeats many more times than normal. These repeats can be used to predict whether someone will develop the illness along with the timeframe in which symptoms of the disease are likely to appear. The more repeats that are present in the gene, the earlier the onset of disease can be expected.
“It has been recognized for some time that repeat expansion mutations can give rise to neurological disorders,” said NINDS investigator, Dr. Sonja Scholz. “But screening for these mutations throughout the entire genome has traditionally been cost-prohibitive and technically challenging.”
The research team screened the entire genomes from large cohorts of FTD/ALS patients and compared them to those of age-matched healthy individuals. While several patients had a well-established genetic marker for FTD/ALS, a small subset unexpectedly had the same huntingtin mutation that is generally associated with Huntington’s disease. However, these individuals did not show the classical symptoms of Huntington’s but rather exhibited symptoms of ALS or FTD.
“None of these patients’ symptoms would have clued their physicians into thinking that the underlying genetic cause was related to the repeat expansion we see in Huntington’s disease,” said Dr. Scholz.
Dr. Scholz further commented that whole genome sequencing is changing how neurological patients can be diagnosed. Traditionally, this has been based on which disease best fit the overall symptoms with treatment aimed at managing those symptoms as best as possible. Now, clinicians can generate genetically defined diagnoses for individual patients, which do not always align with established symptom-based neurological conditions. “Our patients simply don’t match a textbook definition of disease when it comes to which mutation produces which symptoms. Here we have patients carrying a pathogenic huntingtin mutation but who present with FTD or ALS symptoms,” said Dr. Scholz.
One implication of these findings is that these therapies could potentially be applied to the small subset of FTD and ALS patients with that mutation as well. While the overall number of FTD/ALS patients seen with the Huntington’s-linked mutation is small, ranging from 0.12-0.14%, including genetic screening for the mutation to the standard diagnostic procedure for patients showing symptoms of FTD or ALS should be considered.
“Because gene therapy targeting this mutation is already in advanced clinical trials, our work offers real hope to the small number of FTD and ALS patients who carry this mutation,” said Dr. Bryan Traynor, senior investigator, NIA Intramural Research Program. “This type of large-scale international effort showcases the power of genomics in identifying the molecular causes of neurodegenerative diseases and paves the way for personalized medicine.”
Zika virus is a mosquito-borne flavivirus that is transmitted primarily through the bite of an infected Aedes species mosquito. It was originally identified in Africa and later found in tropical regions including South America. Zika can be passed from a pregnant woman to her fetus with an increased incidence of microcephaly and other severe fetal brain defects in babies born to mothers infected during pregnancy.
In 2015, hundreds of children were born with brain deformities resulting from a global outbreak of Zika virus infections. In a recent study, researchers at the National Institutes of Health (NIH) tested more than 10,000 compounds, using advanced drug screening techniques, in search of a cure. Their research showed that a commonly used broad-spectrum antibiotic, methacycline, was effective at preventing brain infections and reducing neurological problems associated with the virus in mice. The study further indicated drugs that were originally designed to treat Alzheimer’s disease and inflammation may also aid in fighting neurological problems caused by Zika infection.
“Around the world, the Zika outbreak produced devastating, long-term neurological problems for many children and their families. Although the infections are down, the threat remains,” said Dr. Avindra Nath, NINDS senior investigator and an author of a study published in PNAS. “We hope these promising results are a good first step to preparing the world for combating the next potential outbreak.”
The study was a collaboration between scientists on Dr. Nath’s team and researchers in laboratories led by Dr. Anton Simeonov, scientific director at the NIH’s National Center for Advancing Translational Sciences (NCATS) and Dr. Radhakrishnan Padmanabhan, Professor of Microbiology & Immunology, Georgetown University Medical Center in Washington, D.C.
The research team investigated drugs that prevent the virus from reproducing by blocking the activity of a protein called NS2B-NS3 Zika virus protease. The Zika virus is a protein capsule that carries long strings of RNA-encoded instructions for manufacturing more viral proteins. During an infection, the virus injects the RNA into a cell, resulting in the production of these proteins, which are strung together, side-by-side, like the parts in a plastic model airplane kit. The NS2B-NS3 protease then snaps off each protein, all of which are critical for assembling new viral particles.
“Proteases act like scissors. Blocking protease activity is an effective strategy for counteracting many viruses,” said Dr. Rachel Abrams, an organic chemist in Dr. Nath’s lab and the study leader. “We wanted to look as far and wide as possible for drugs that could prevent the protease from snipping the Zika virus polyprotein into its active pieces.”
To find potential drug candidates, the team created assays for assessing their ability to block NS2B-NS3 Zika virus protease activity. Each assay was tailored to a different screening, or sifting, technique. They then used these assays to simultaneously screen thousands of drug candidates stored in three separate libraries. A preliminary screen of 2,000 compounds suggested that the commonly used, tetracycline-based antibiotic drugs, like methacycline, may be effective at blocking the protease.
A large-scale screen of more than 10,000 compounds further helped identify an investigational anti-inflammatory medicine, called MK-591, and a failed anti-Alzheimer’s disease drug, called JNJ-404 as potential candidates. A virtual screen of over 130,000 compounds was also used to identify additional drug candidates. The virtual candidate screening was achieved by entering the results of the initial screening efforts into a computer and then using artificial intelligence based programs to model the effective components of the compounds that demonstrated the ability to block NS2B-NS3 Zika virus protease activity. “These results show that taking advantage of the latest technological advances can help researchers find treatments that can be repurposed to fight other diseases,” said Dr. Simeonov.
The Zika virus is known to preferentially infect stem cells in the brain, leading scientists to suspect this to be the reason why infections cause more harm to newborn babies than to adults. Experiments using neural stem cells grown in petri dishes indicated that all three drugs identified in this study may counteract these problems. Treating the cells with methacycline, MK-591, or JNJ-404 reduced Zika virus infections.
Because tetracyclines are FDA approved drugs that are known to cross the placenta of pregnant women, the researcher team focused on methacycline and found that it may reduce some neurodevelopmental problems caused by the Zika virus. Zika-infected newborn mice that were treated with methacycline showed better balance and the ability to turn over more easily than ones that were given a placebo. Brain examinations suggested this was because the antibiotic reduced infections and neural damage. However, the antibiotics did not completely counteract the negative effects caused by the Zika virus. The team also observed that the weight of mice infected with the virus was lower than control mice regardless of whether the mice were treated with methacycline.
“These results suggest that tetracycline-based antibiotics may at least be effective at preventing the neurological problems associated with Zika virus infections,” said Dr. Abrams. “Given that they are widely used, we hope that we can rapidly test their potential in clinical trials.”
Associate director for Clinical Research
NIAID Division of Microbiology and Infectious Diseases
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