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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Hitting the Right Target? Lab Studies Suggest Epigenetic Drug May Fight Childhood Brain Cancer

Faces of DIPG

Caption: Remembering a few of the many children who’ve died of DIPG; Left, Lyla Nsouli and parents; upper right, Andrew Smith and mom; lower right, Alexis Agin and parents.
Credits: Nsouli, Smith, and Agin families

Every year in the United States, several hundred children and their families receive a devastating diagnosis: diffuse intrinsic pontine glioma (DIPG). Sadly, this inoperable tumor of the brain stem, little known by the public, is almost always fatal, and efforts to develop life-saving treatments have been hampered by a lack of molecular data to identify agents that might specifically target DIPG. In fact, more than 200 clinical trials of potential drugs have been conducted in DIPG patients without any success.

Now, using cell lines and mouse models created with tumor tissue donated by 16 DIPG patients, an international research coalition has gained a deeper understanding of this childhood brain cancer at the molecular level. These new preclinical tools have also opened the door to identifying more precise targets for DIPG therapy, including the exciting possibility of using a drug already approved for another type of cancer.

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LabTV: Curious about the Aging Brain

Saul Villeda

This LabTV video takes us to the West Coast to meet Saul Villeda, a creative young researcher who’s exploring ways to reduce the effects of aging on the human brain. Thanks to a 2012 NIH Director’s Early Independence award, Villeda set up his own lab at the University of California, San Francisco to study how age-related immune changes may affect the ability of brain cells to regenerate. By figuring out exactly what’s going on, Villeda and his team hope to devise ways to counteract such changes, possibly preventing or even reversing the cognitive declines that all too often come with age.

Villeda is the first person in his family to become a scientist. His parents immigrated to the United States from Guatemala, settled into a working-class neighborhood in Pasadena, CA, and enrolled their kids in public schools. While he was growing up, Villeda says he’d never even heard of a Ph.D. and thought all doctors were M.D.’s who wore stethoscopes. But he did have a keen mind and a strong sense of curiosity—gifts that helped him become the valedictorian of his high school class and find his calling in science. Villeda went on to earn an undergraduate degree in physiological science from the University of California, Los Angeles and a Ph.D. in neurosciences from Stanford University Medical School, Palo Alto, CA, as well as to publish his research findings in several influential scientific journals.

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What Is Obesity? Metabolic Signatures Offer New Comprehensive View

Silhouettes over an NMR

Credit: Adapted from Elliott, P et al., Sci Transl Med. 2015 Apr 29;7(285)

As obesity has risen in the United States and all around the world, so too have many other obesity-related health conditions: diabetes, heart disease, stroke, cancer, and maybe even Alzheimer’s disease. But how exactly do those extra pounds lead to such widespread trouble, and how might we go about developing better ways to prevent or alleviate this very serious health threat?

In a new study in Science Translational Medicine [1], researchers performed sophisticated analyses of the molecules excreted in human urine to produce one of the most comprehensive pictures yet of the metabolic signature that appears to correlate with obesity. This work provides a fascinating preview of things to come as researchers from metabolomics, microbiomics, and a wide variety of other fields strive to develop more precise approaches to managing and preventing disease.

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