Research advances from the National Institutes of Health (NIH) Intramural Research Program (IRP) often make headlines. Read the news releases that describe our most recent findings:
Whether you’re shedding pounds with the help of effective new medicines, slimming down after weight loss surgery or cutting calories and adding exercise, there will come a day when the numbers on the scale stop going down, and you hit the dreaded weight loss plateau.
In a recent study, Kevin Hall, a researcher at the National Institutes of Health who specializes in measuring metabolism and weight change, looked at when weight loss typically stops depending on the method people were using todrop pounds. He broke down the plateau into mathematical models using data from high-quality clinical trials of different ways to lose weight to understand why people stop losing when they do. The study published Monday in the journal Obesity.
IRP study results represent major advance for structure-based HIV vaccine design
An experimental vaccine regimen based on the structure of a vulnerable site on HIV elicited antibodies in mice, guinea pigs and monkeys that neutralize dozens of HIV strains from around the world. The findings were reported today in the journal Nature Medicine by researchers at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and their colleagues.
Peter D. Kwong, Ph.D., and John R. Mascola, M.D., led the study. Dr. Kwong is chief of the Structural Biology Section at the NIAID Vaccine Research Center, and Dr. Mascola is the center director.
“NIH scientists have used their detailed knowledge of the structure of HIV to find an unusual site of vulnerability on the virus and design a novel and potentially powerful vaccine,” said NIAID Director Anthony S. Fauci, M.D. “This elegant study is a potentially important step forward in the ongoing quest to develop a safe and effective HIV vaccine.”
This protein structure diagram illustrates the location of the fusion peptide epitope (red) on the HIV spike (green), which projects out of the viral membrane (grey). The diagram also shows how a broadly neutralizing antibody (yellow) binds to the fusion peptide.
A novel approach to immunotherapy developed by researchers at the National Cancer Institute (NCI) has led to the complete regression of breast cancer in a patient who was unresponsive to all other treatments. This patient received the treatment in a clinical trial led by Steven A. Rosenberg, M.D., Ph.D., chief of the Surgery Branch at NCI’s Center for Cancer Research (CCR), and the findings were published June 4, 2018 in Nature Medicine. NCI is part of the National Institutes of Health.
“We’ve developed a high-throughput method to identify mutations present in a cancer that are recognized by the immune system,” Dr. Rosenberg said. “This research is experimental right now. But because this new approach to immunotherapy is dependent on mutations, not on cancer type, it is in a sense a blueprint we can use for the treatment of many types of cancer.”
The new immunotherapy approach is a modified form of adoptive cell transfer (ACT). ACT has been effective in treating melanoma, which has high levels of somatic, or acquired, mutations. However, it has been less effective with some common epithelial cancers, or cancers that start in the lining of organs, that have lower levels of mutations, such as stomach, esophageal, ovarian, and breast cancers.
Left: MRI scans of a woman with breast cancer before TIL therapy show a lesion invading the chest wall (top) and metastatic lesions in the liver (bottom). Right: Scans 14 months after treatment show all lesions have disappeared.
IRP study finds Information integration trumps emotional, sensory, motor functions
Some human brains are nearly twice the size of others — but how might that matter? Researchers at the National Institute of Mental Health (NIMH) and their NIH grant-funded colleagues have discovered that these differences in size are related to the brain’s shape and the way it is organized. The bigger the brain, the more its additional area is accounted for by growth in thinking areas of the cortex, or outer mantle – at the expense of relatively slower growth in lower order emotional, sensory, and motor areas.
This mirrors the pattern of brain changes seen in evolution and individual development – with higher-order areas showing greatest expansion. The researchers also found evidence linking the high-expanding regions to higher connectivity between neurons and higher energy consumption.
“Just as different parts are required to scale-up a garden shed to the size of a mansion, it seems that big primate brains have to be built to different proportions,” explained Armin Raznahan, M.D., Ph.D., of the NIMH Intramural Research Program (IRP). “An extra investment has to be made in the part that integrates information – but that’s not to say that it’s better to have a bigger brain. Our findings speak more to the different organizational needs of larger vs. smaller brains.”
Larger human brains show relatively more growth in integrative cortex areas (red) than smaller human brains – at a cost of relatively less growth in lower sensory, motor and emotion processing areas.
IRP study suggests the importance of preconception vitamin D in maintaining pregnancy
Among women planning to conceive after a pregnancy loss, those who had sufficient levels of vitamin D were more likely to become pregnant and have a live birth, compared to women with insufficient levels of the vitamin, according to an analysis by researchers at the National Institutes of Health. This study appears in The Lancet Diabetes & Endocrinology.
The authors note that a few studies have shown that women who have higher levels of vitamin D before undergoing in vitrofertilization have higher pregnancy rates than those with lower levels. However, little research has been done on pregnancy rates and pregnancy loss in women attempting to conceive without assisted reproductive technologies.
Francisella tularensis is the bacterium that causes tularemia, a life-threatening disease spread to humans via contact with an infected animal or through mosquito, tick or deer fly bites. As few as 10 viable bacteria can cause the disease, which has a death rate of up to 60 percent. Scientists from the National Institute of Allergy and Infectious Diseases — part of the National Institutes of Health — have unraveled the process by which the bacteria cause disease. They found that F. tularensis tricks host cell mitochondria, which produce energy for the cell, in two different phases of infection. In the first eight hours of infection, the bacteria increase mitochondria function, which inhibits cell death and prevents the cell from mounting an inflammatory response to avoid an immune system attack. In the 24 hours after, the bacteria impair mitochondrial function, undergo explosive replication and spread. These basic science findings could play a role in developing effective treatment strategies, according to the researchers.
Previously, researchers discovered that F. tularensis could inhibit inflammation following infection of immune system cells called macrophages, but they did not understand how it occurred. The new study, published in Infection and Immunity, illuminates that process, confirming that the bacterium’s manipulation of the mitochondrial machinery in the host cell is required to block strong inflammatory responses. Also, the researchers show that the timing of the manipulation of the mitochondria machinery during infection is important to how the bacteria control host cell death. The researchers also said this could be the first study to show that a bacterium’s sugar-like protective outer capsule, or polysaccharide, can increase mitochondria function, in this case, during early infection.
Study yields potential clues to understanding eye disease and blindness in people
Loss of eye tissue in blind cavefish (Astyanax mexicanus), which occurs within a few days of their development, happens through epigenetic silencing of eye-related genes, according to a study led by the National Institutes of Health. Epigenetic regulation is a process where genes are turned off or on, typically in a reversible or temporary manner. This mechanism differs from genetic mutations, which are permanent changes in the DNA code. The study appears in Nature Ecology & Evolution.
“Subterranean animals provide a unique opportunity to study how animals thrive in extreme environments, some of which can mimic human disease conditions,” said Brant M. Weinstein, Ph.D., senior investigator at NIH’s Eunice Kennedy ShriverNational Institute of Child Health and Human Development (NICHD) and one of the study authors. “Many of the cavefish genes identified in our study are also linked to human eye disorders, suggesting these genes are conserved across evolution and may be similarly regulated in people.”
Photographs of Astyanax mexicanus, surface form with eyes (top) and cave form without eyes (bottom).
A new study published in the May 2018 issue of Preventive Medicine shows that African Americans and Latinos are significantly more likely to experience serious depression than Whites, but chronic stress does not seem to explain these differences. Dr. Eliseo J. Pérez-Stable, director of the National Institute on Minority Health and Health Disparities (NIMHD) was the senior author of the study, which also found that African Americans and Latinos were more likely to have higher levels of chronic stress and more unhealthy behaviors. NIMHD is part of the National Institutes of Health.
To examine the relationship between unhealthy behaviors, chronic stress, and risk of depression by race and ethnicity, researchers used data collected on 12,272 participants, aged 40 to 70 years, from 2005 to 2012. These data were part of the National Health and Nutrition Examination Survey (NHANES), a nationally representative health interview and examination survey of U.S. adults. This age range population was selected for this study to capture the effects of chronic stress over the lifetime of the participants.
“Understanding the social and behavioral complexities associated with depression and unhealthy behaviors by race/ethnicity can help us understand how to best improve overall health,” said Pérez-Stable.
Researchers have shown that pain-induced changes in the rat brain’s opioid receptor system may explain the limited effectiveness of opioid therapy in chronic pain and may play a role in the depression that often accompanies it. These findings clearly show the impact of chronic pain on the brain and its relation to depression. The study, conducted by scientists at the National Institutes of Health (NIH) and colleagues from McGill University, Montreal, Quebec, Canada, was published in the journal Pain.
“We know that people with chronic pain have reduced availability of opioid receptors — the molecules opioid drugs bind to — in the brain,” said Mark Pitcher, Ph.D., visiting fellow in the Division of Intramural Research at the National Center for Complementary and Integrative Health (NCCIH) and one of the authors of the study. “What we haven’t known ― until now ― is why. Are there preexisting brain differences that might predispose some people to develop chronic pain? Or might chronic pain cause these differences? Our findings suggest that chronic pain itself is responsible.”
In the study, cross-sectional positron emission tomography (PET) imaging was performed on the brains of 17 rats that had undergone surgery to produce a nerve injury that causes chronic pain and on 17 rats that had undergone sham surgery (a similar procedure that does not cause chronic pain). Three months later, the availability of opioid receptors had decreased in multiple regions of the brain in the nerve-injured rats, but no changes had occurred in the sham-surgery rats.
Scientists have found a connection between bacteria in the gut and antitumor immune responses in the liver. Their study, published online May 24 in Science, was led by researchers in the Center for Cancer Research (CCR) at the National Cancer Institute (NCI). It showed that bacteria found in the gut of mice affect the liver’s antitumor immune function. The findings have implications for understanding the mechanisms that lead to liver cancer and for therapeutic approaches to treat them. NCI is part of the National Institutes of Health.
“What we found using different tumor models is that if you treat mice with antibiotics and thereby deplete certain bacteria, you can change the composition of immune cells of the liver, affecting tumor growth in the liver,” said Tim Greten, M.D., of NCI’s CCR, who led the study. “This is a great example of how what we learn from basic research can give us insight into cancer and possible treatments.”
The microbiome is the collection of bacteria and other microorganisms that live in or on the body. In humans, the greatest proportion of the body’s total microbiome is in the gut. Despite extensive research into the relationship between the gut microbiome and cancer, the role of gut bacteria in the formation of liver cancer has remained poorly understood.
Scientists developed monoclonal antibody from Ebola survivor
A first-in-human trial evaluating an experimental treatment for Ebola virus disease has begun at the National Institutes of Health Clinical Center in Bethesda, Maryland. The Phase 1 clinical trial is examining the safety and tolerability of a single monoclonal antibody called mAb114, which was developed by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH, and their collaborators. Investigators aim to enroll between 18 and 30 healthy volunteers aged 18 to 60. The trial will not expose participants to Ebola virus.
Ebola virus disease is a serious and often fatal illness that can cause fever, headache, muscle pain, weakness, fatigue, diarrhea, vomiting, stomach pain and hemorrhage (severe bleeding). It was first discovered in humans in 1976 in the Democratic Republic of the Congo (DRC) and has caused periodic cases and outbreaks in several African countries since then. The largest outbreak, which occurred in West Africa from 2014 to 2016, caused more than 28,600 infections and more than 11,300 deaths, according to the World Health Organization. In May 2018, the DRC reported an Ebola outbreak, located in Équateur Province in the northwest of the country. As of May 20, health officials have reported 51 probable or confirmed cases and 27 deaths. There are currently no licensed treatments available for Ebola virus disease, although multiple experimental therapies are being developed.
“We hope this trial will establish the safety of this experimental treatment for Ebola virus disease — an important first step in a larger evaluation process,” said NIAID Director Anthony S. Fauci, M.D. “Ebola is highly lethal, and reports of another outbreak in the DRC remind us that we urgently need Ebola treatments.”
