Creative Minds: Using Machine Learning to Understand Genome Function

Anshul Kundaje

Anshul Kundaje / Credit: Nalini Kartha

Science has always fascinated Anshul Kundaje, whether it was biology, physics, or chemistry. When he left his home country of India to pursue graduate studies in electrical engineering at Columbia University, New York, his plan was to focus on telecommunications and computer networks. But a course in computational genomics during his first semester showed him he could follow his interest in computing without giving up his love for biology.

Now an assistant professor of genetics and computer science at Stanford University, Palo Alto, CA, Kundaje has received a 2016 NIH Director’s New Innovator Award to explore not just how the human genome sequence encodes function, but also why it functions in the way that it does. Kundaje even envisions a time when it might be possible to use sophisticated computational approaches to predict the genomic basis of many human diseases.

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Creative Minds: Mapping the Biocircuitry of Schizophrenia and Bipolar Disorder

Bruce Yankner

Bruce Yankner

As a graduate student in the 1980s, Bruce Yankner wondered what if cancer-causing genes switched on in non-dividing neurons of the brain. Rather than form a tumor, would those genes cause neurons to degenerate? To explore such what-ifs, Yankner spent his days tinkering with neural cells, using viruses to insert various mutant genes and study their effects. In a stroke of luck, one of Yankner’s insertions encoded a precursor to a protein called amyloid. Those experiments and later ones from Yankner’s own lab showed definitively that high concentrations of amyloid, as found in the brains of people with Alzheimer’s disease, are toxic to neural cells [1].

The discovery set Yankner on a career path to study normal changes in the aging human brain and their connection to neurodegenerative diseases. At Harvard Medical School, Boston, Yankner and his colleague George Church are now recipients of an NIH Director’s 2016 Transformative Research Award to apply what they’ve learned about the aging brain to study changes in the brains of younger people with schizophrenia and bipolar disorder, two poorly understood psychiatric disorders.

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Snapshots of Life: Muscling in on Development

Limb Muscles

Credit: Mary P. Colasanto, University of Utah, Salt Lake City

Twice a week, I do an hour of weight training to maintain muscle strength and tone. Millions of Americans do the same, and there’s always a lot of attention paid to those upper arm muscles—the biceps and triceps. Less appreciated is another arm muscle that pumps right along during workouts: the brachialis. This muscle—located under the biceps—helps your elbow flex when you are doing all kinds of things, whether curling a 50-pound barbell or just grabbing a bag of groceries or your luggage out of the car.

Now, scientific studies of the triceps and brachialis are providing important clues about how the body’s 40 different types of limb muscles assume their distinct identities during development [1]. In these images from the NIH-supported lab of Gabrielle Kardon at the University of Utah, Salt Lake City, you see the developing forelimb of a healthy mouse strain (top) compared to that of a mutant mouse strain with a stiff, abnormal gait (bottom).

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Molecular Answers Found for a Mysterious Rare Immune Disorder

Harry Hill and Patient Images

Caption: Helping to solve a medical mystery. Top left, University of Utah’s Harry Hill; Bottom, CVID patient Roma Jean Ockler; Right, Ockler showing the medication that helps to control her CVID.
Credit: Jeffrey Allred, Deseret News

When most of us come down with a bacterial infection, we generally bounce back with appropriate treatment in a matter of days. But that’s often not the case for people who suffer from common variable immunodeficiency (CVID), a group of rare disorders that increase the risk of life-threatening bacterial infections of the lungs, sinuses, and intestines. CVID symptoms typically arise in adulthood and often take many years to diagnose and treat, in part because its exact molecular causes are unknown in most individuals.

Now, by combining the latest in genomic technology with some good, old-fashioned medical detective work, NIH-funded researchers have pinpointed the genetic mutation responsible for an inherited subtype of CVID characterized by the loss of immune cells essential to the normal production of antibodies [1]. This discovery, reported recently in The New England Journal of Medicine, makes it possible at long last to provide a definitive diagnosis for people with this CVID subtype, paving the way for them to receive more precise medical treatment and care. More broadly, the new study demonstrates the power of precision medicine approaches to help the estimated 25 to 30 million Americans who live with rare diseases [2].

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A New Tool in the Toolbox: New Method Traces Free-Floating DNA Back to Its Source

Graphic

Caption: DNA (blue) loops around nucleosomes (gray) and is bound by transcription factors (red), proteins that switch genes on and off and act in a tissue-specific manner. When cells die, enzymes (scissors) chop up areas between the nucleosomes and transcription factors, releasing DNA fragments in unique patterns. By gathering the released DNA fragments in blood, researchers can tell which types of cells produced them.
Credit: Shendure Lab/University of Washington

When cells die, scissor-like enzymes snip their DNA into tiny fragments that leak into the bloodstream and other bodily fluids. Researchers have been busy in recent years working on ways to collect these free-floating bits of DNA and explore their potential use in clinical care.

These approaches, sometimes referred to as “liquid biopsies,” hinge on the ability to distinguish specific DNA fragments from the body’s normal background of “cell-free” DNA, most of which comes from dying white blood cells. Seeking other sources for cell-free DNA in particular situations is beginning to bear fruit, however. Current applications include: 1) a test in maternal blood to look for DNA from the fetus (actually from the fetal component of the placenta), which provides a means of detecting a possible genetic abnormality; 2) a test in a cancer patient’s blood to look for cancer-specific mutations, as a way of assessing response to treatment or early signs of relapse; and 3) a test in an organ transplant recipient, where increasing abundance of DNA fragments from the donor can be an early sign of rejection.

But recent proposals have been floated about looking for cell-free DNA in healthy individuals, as an early sign of some health problems. Suppose something was found—how could you know the source? Now a team of NIH-funded researchers has devised a new method that uses distinctive features of DNA packaging to provide an additional layer of information about the origins of free-floating DNA, vastly expanding the potential uses for such tests [1].

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