Imaging Advance Offers New View on Allergic Asthma

Healthy vs. Allergic Asthma Airways

Caption: OR-OCT images of the airways of a healthy person (left) and a person with allergic asthma (right). The colorized portion highlights airway smooth muscle, with thinner areas in purple and black and thicker areas in yellow and orange. Credit: Cho et al., Science Translational Medicine (2016)

You probably know people who sneeze a little when they encounter plant pollens, pet dander, or other everyday allergens. For others, however, these same allergens can trigger a serious asthma attack that can make breathing a life-or-death struggle. Now, two NIH-funded research groups have teamed up to help explain the differences in severity underlying the two types of reactions.

In the studies, researchers at Massachusetts General Hospital, Boston, used an innovative imaging tool to zoom in on a person’s airways safely in real time to gain an unprecedented view of how his or her body reacts to allergens [1,2]. The imaging revealed key differences between the asthma and non-asthma groups in the smooth muscle tissue that surrounds critical airways, and is responsible for constriction. In a complementary series of experiments, researchers also uncovered heightened immune responses in the airways of folks with allergic asthma. The findings offer important new clues in the quest to better understand and guide treatment for asthma, a condition that affects more than 300 million people around the world.

The factors driving airway constriction in people with asthma have been poorly understood in part because, until now, there hasn’t been a way to view airway smooth muscle in action. As described in the journal Science Translational Medicine, Melissa Suter and colleagues adapted an established form of imaging called optical coherence tomography (OCT) to help fill this gap. Standard OCT produces an image by measuring the amount of light reflected back from body tissues, but such images aren’t sufficient to distinguish airway smooth muscle from other tissues.

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Largest Study Yet Shows Mother’s Smoking Changes Baby’s Epigenome

Pregnant woman smoking

Credit: Daniel Berehulak/Getty Images

Despite years of public health campaigns warning of the dangers of smoking when pregnant, many women are unaware of the risk or find themselves unable to quit. As a result, far too many babies are still being exposed in the womb to toxins that enter their mothers’ bloodstreams when they inhale cigarette smoke. Among the many infant and child health problems that have been linked to maternal smoking are premature birth, low birth weight, asthma, reduced lung function, sudden infant death syndrome (SIDS), and cleft lip and/or palate.

Now, a large international study involving NIH-supported researchers provides a biological mechanism that may explain how exposure to cigarette toxins during fetal development can produce these health problems [1]. That evidence centers on the impact of the toxins on the epigenome of the infant’s body tissues. The epigenome refers to chemical modifications of DNA (particularly methylation of cytosines), as well as proteins that bind to DNA and affect its function. The genome of an individual is the same in all cells of their body, but the epigenome determines whether genes are turned on or off in particular cells. The study found significant differences between the epigenetic patterns of babies born to women who smoked during pregnancy and those born to non-smokers, with many of the differences affecting genes known to play key roles in the development of the lungs, face, and nervous system.

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Cystic Fibrosis: Keeping the Momentum Going

Cystic Fibrosis: 1989 and 2015

Caption: Lower left, me, Lap-Chee Tsui, and John Riordan celebrating our discovery of the cystic fibrosis gene. Right, Robert J. Beall, me, and Doris Tulcin at a November Cystic Fibrosis Foundation event honoring Dr. Beall.

It’s been more than a quarter-century since my colleagues and I were able to identify the gene responsible for cystic fibrosis (CF), a life-shortening inherited disease that mainly affects the lungs and pancreas [1]. And, at a recent event in New York, I had an opportunity to celebrate how far we’ve come since then in treating CF, as well as to honor a major force behind that progress, Dr. Bob Beall, who has just retired as president and chief executive officer of the Cystic Fibrosis Foundation.

Thanks to the tireless efforts of Bob and many others in the public and private sectors to support basic, translational, and clinical research, we today have two therapies from Vertex Pharmaceuticals that are targeted specifically at CF’s underlying molecular cause: ivacaftor (Kalydeco™), approved by the Food and Drug Administration (FDA) in 2012 for people with an uncommon mutation in the CF gene; and the combination ivacaftor-lumacaftor (Orkambi™), approved by the FDA in July for the roughly 50 percent of CF patients with two copies of the most common mutation. Yet more remains to be done before we can truly declare victory. Not only are new therapies needed for people with other CF mutations, but also for those with the common mutation who don’t respond well to Orkambi™. So, the work needs to go on, and I’m encouraged by new findings that suggest a different strategy for helping folks with the most common CF mutation.

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Targeting Cystic Fibrosis: Are Two Drugs Better than One?

Cystic Fibrosis Patient

Caption: Doctor with a child with cystic fibrosis who is taking part in clinical research studies. Credit: Colorado Clinical and Translational Sciences Institute

To explain the many challenges involved in turning scientific discoveries into treatments and cures, I often say, “Research is not a 100-yard dash, it’s a marathon.” Perhaps there is no better example of this than cystic fibrosis (CF). Back in 1989, I co-led the team that identified the cystic fibrosis transmembrane conductance regulator (CFTR) genethe gene responsible for this life-shortening, inherited disease that affects some 70,000 people worldwide [1]. Yet, it has taken more than 25 years of additional basic, translational, and clinical research to reach the point where we are today: seeing the emergence of precise combination drug therapy that may help about half of all people with CF.

CF is a recessive diseasethat is, affected individuals have a misspelling of both copies of CFTR, one inherited from each parent; the parents are asymptomatic carriers. The first major advance in designer drug treatment for CF came in 2012, when the Food and Drug Administration (FDA) approved ivacaftor (Kalydeco™), the first drug to target specifically CF’s underlying molecular cause [2]. Exciting news, but the rub was that ivacaftor was expected to help only about 4 percent of CF patients—those who carry a copy of the relatively rare G551D mutation (that means a normal glycine at position 551 in the 1480 amino acid protein has been changed to aspartic acid) in CFTR. What could be done for the roughly 50 percent of CF patients who carry two copies of the far more common F508del mutation (that means a phenylalanine at position 508 is missing)? New findings show one answer may be to team ivacaftor with an experimental drug called lumacaftor.

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Creative Minds: Harnessing Technologies to Study Air Pollution’s Health Risks

Perry Hystad

Perry Hystad
Credit: Hannah O’Leary, Oregon State University

After college, Perry Hystad took a trip to India and, while touring several large cities, noticed the vast clouds of exhaust from vehicles, smoke from factories, and soot from biomass-burning cook stoves. As he watched the rapid urban expansion all around him, Hystad remembers thinking: What effect does breathing such pollution day in and day out have upon these people’s health?

This question stuck with Hystad, and he soon developed a profound interest in environmental health. In 2013, Hystad completed his Ph.D. in his native Canada, studying the environmental risk factors for lung cancer [1, 2, 3]. Now, with the support of an NIH Director’s Early Independence Award, Hystad has launched his own lab at Oregon State University, Corvallis, to investigate further the health impacts of air pollution, which one recent analysis indicates may contribute to as many as several million deaths worldwide each year [4].

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