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Melanoma Therapy Shows Promise

James Allison: Investigator; Memorial Sloan-Kettering Cancer Center

For the first time, a drug has been shown in a clinical trial to extend the lives of patients with stage III and IV melanoma. Called ipilimumab, the drug liberates the immune system from a molecule that usually reins it in, leaving T cells free to do an important job: attack tumors. That molecule, called CTLA-4, was discovered in Jim Allison’s University of California, Berkeley, lab 15 years ago. In work that provided the foundation for ipilimumab’s development, Allison showed that blocking CTLA-4 could ramp up the immune response to cancer without causing T cells to mount a lethal attack against the body’s own tissues. Ipilimumab demonstrates that immunotherapy can be better than any other kind of therapy—including radiation, chemotherapy, and targeted therapies—in the treatment of this fatal disease.

Toward a Mouse Model for OCD

Mario Capecchi: Investigator; University of Utah

Shahin Rafii: Investigator; Weill Cornell Medical College

Studies in mice have brought scientists closer to understanding the origins of obsessive-compulsive disorder (OCD). Mario Capecchi’s group discovered that a bone marrow transplant can eliminate pathological behaviors in mice with an OCD-like condition, for the first time directly linking the immune system to a behavioral disorder. The animals’ obsessive grooming and hair-pulling is due to a defect in microglia—cells that begin their lives in the bone marrow and then migrate through the blood to protect the brain and spinal cord.

Another mouse model for OCD was created in Shahin Rafii’s lab when his team switched off a gene that is most active in the brain but is also turned on in vascular, leukemic, and blood stem cells. The mice appeared anxious and had patterns of brain activity that closely mirror those in people with OCD. The new mouse line could be useful in searching for better drugs to treat the condition.

Neural Chatter Comes to Light

Loren Looger: Group Leader; Janelia Farm

Identifying the networks of neurons necessary for even simple tasks is a key goal for scientists studying how the brain’s architecture enables behavior—but the tangled pathways can be nearly impossible to trace. A new tool allows neuroscientists to watch individual neurons light up as they communicate with one another to control an animal’s behavior. Through genetic manipulation, scientists compelled neurons to manufacture fluorescent signaling molecules activated by the influx of calcium that accompanies a nerve impulse. The new tool, already used in flies, worms, and mice, is brighter and more sensitive than previously available genetically encoded calcium indicators.

Enzyme Gives Cells a Fresh Start

Yi Zhang: Investigator; University of North Carolina

When a sperm enters an egg during fertilization, almost all the methylation marks—chemical flags that signal that a gene should stay off—are erased from its DNA. This wipes clean the slate for gene regulation, so decisions that will determine the fate of developing cells can be made later. Researchers identified an enzyme that can prompt this genetic reformatting. Whether the enzyme instigates these changes during fertilization remains unclear, but it could help scientists create stem cells from adult cells in the body or arrest the progression of cancers by reactivating genes that keep cell growth under control.

Understanding How Damaged Hearts Heal

Kenneth Poss: Early Career Scientist; Duke University

Mark Krasnow: Investigator; Stanford University

Studies in mice and fish are providing clues that could one day help scientists rebuild damaged human hearts. Bypass grafts that keep blood flowing in patients with coronary artery disease eventually wear out, and the scar tissue a heart builds after a nonfatal heart attack patches the injury but can’t pump. Zebrafish cope with cardiac injury much better, and by tracking the activity of particular cells as the animals regenerated heart tissue, Kenneth Poss and colleagues began to decipher instructions the cells use to carry out their repair work.

In mouse studies, Mark Krasnow and his team determined that during development, coronary arteries originate from the sinus venosus, the large vein that returns blood to an embryo’s heart. The work hints at which cells scientists might target to induce the body to rebuild its own damaged arteries.

Delivery Method Shapes Baby’s Bacteria

Rob Knight: Early Career Scientist; University of Colorado

Rapid-fire gene sequencing revealed that bacterial communities inhabiting babies delivered via Cesarean section are different than the bacteria carried by babies born vaginally. In samples collected from the babies and their mothers, researchers examined a gene that is present in all bacteria but that differs from species to species. The resulting bacterial fingerprints revealed that delivery methods influenced which of the mothers’ microbes were passed on to the infants. The finding could explain why C-section babies experience more allergies, asthma, and infections with the difficult-to-treat methicillin-resistant Staphylococcus aureus (MRSA).

Worldwide Search Yields Eye Disorder’s Roots

Elizabeth Engle: Investigator; Children’s Hospital Boston

A search across five continents for children with a rare eye movement disorder culminated in identification of the disorder’s genetic cause. Children with the inherited disease, called congenital fibrosis of the extraocular muscle type 3, have drooping eyelids and are unable to move their eyes fully. Once scientists identified 29 families with the disorder, they could link it to a gene encoding a protein that helps neurons navigate a developing nervous system and connect with the appropriate cells. Mutations in the gene can cause other errors in neurodevelopment and neuronal survival, so the study has defined a new series of neurological disorders.

The Narrow Human-Neandertal Divide

Greg Hannon: Investigator; Cold Spring Harbor Laboratory

A 49,000-year-old bone flake found in a Spanish cave revealed astonishingly few differences between the proteins encoded by the DNA of modern humans and those of their thick-bodied ancestors, the Neandertals. Although 99.8 percent of the DNA extracted from the bone was from bacteria, fungi, and other contaminants, a new technique for isolating and sequencing targeted stretches of DNA enabled researchers to analyze the 14,000 genes that have changed in humans since their evolutionary split with chimpanzees. Differences in the genetic code indicated that just 88 of the proteins encoded by those genes differed by at least one amino acid between the two groups.

Nursing Lab-Grown Liver Cells

Sangeeta Bhatia: Investigator; MIT

The hepatitis C virus (HCV) can live for decades inside a patient’s liver—sometimes destructively, sometimes causing little noticeable harm—but scientists have struggled to keep the virus alive for more than a few days outside the body. By reproducing the network of supportive cells and other factors that allow liver cells to thrive in the body, scientists engineered the first cell culture system that sustains HCV infection in its natural host—noncancerous hepatocytes—for several weeks. The system will help researchers learn more about how the virus infects liver cells and will allow for more efficient preclinical screening of potential drugs.

Preeclampsia May Set Stage for Thyroid Trouble

S. Ananth Karumanchi: Investigator; Beth Israel Deaconess Medical Center

Delivering a baby early can put an end to preeclampsia, the dangerously high blood pressure and associated symptoms that complicate some pregnancies. But a new study found that preeclampsia has lingering health consequences that can manifest themselves decades later. Researchers found that for women with a history of recurrent preeclampsia, the risk of thyroid problems later in life is almost one in five—three times higher than for women overall. The study’s authors recommend that at-risk women be monitored for the easily treated condition, which can cause weight gain, fatigue, and elevated cholesterol.

Genetic Mix-Up Feeds Cancer

Arul Chinnaiyan: Investigator; University of Michigan

A newly identified set of hybrid genes, created when chromosomes reshuffle their genetic material and place one gene under the inappropriate control of another, may accelerate the growth of certain cancers. Although the resultant hybrid proteins are rare, they are associated with particularly aggressive forms of prostate cancer, gastric cancer, and melanoma, and they belong to a class of molecules considered good drug targets. Identifying rare mutations such as these could help researchers design drugs that will benefit patients whose cancers are driven by the hybrid proteins.

DNA Sequencing ID’s Disease

Richard Lifton: Investigator; Yale School of Medicine

For the first time, scientists diagnosed a genetic disease by sequencing all of a patient’s protein-coding DNA. Although only about 1 percent of an individual’s DNA serves as a blueprint for protein production, once the team had isolated that small fraction, they still had about 34 million base pairs of DNA to analyze. Today’s rapid DNA sequencing technology made the search possible. Just 10 days after receiving the DNA, the team found a mutation that affected electrolyte transport in the patient’s intestines. Their diagnosis of a condition called congenital chloride diarrhea was confirmed clinically, and doctors were able to provide a treatment tailored to the disease.

Some Fly Cells Are Gender-Blind

Bruce Baker: Group Leader; Janelia Farm

Unless you’re a geneticist or an insect interested in courtship, you may never contemplate the gender of a fruit fly. In flies themselves, most cells are equally clueless about males and females. Until recently, scientists suspected that the master switch that tells female cells to create female characteristics and male cells to create male ones—a gene called doublesex—was present in the same gender-specific form in every cell of an individual fruit fly. But when they tracked the protein in developing animals, researchers found a surprise: In body parts with no overt differences between males and females, doublesex wasn’t even turned on in most cells—meaning that those cells are identical regardless of the organism’s gender.

Concerns Ease on Malaria Drug

Abdoulaye Djimdé: International Research Scholar; University of Bamak

Concerns about the likelihood of an existing drug encouraging the spread of drug-resistant malaria parasites may have been overstated. The drug, sulfadoxine-pyrimethamine (SP), is used to treat and prevent malaria in pregnant women. It has not been administered more widely for fear that such use could accelerate the parasite’s resistance to SP and render the drug useless. However, new research showed that parasites exposed to the drug often fail to reach the mature stage at which they can infect mosquitoes—meaning they can’t readily be spread to additional humans. This could mean that SP can be used to treat infants and children without causing widespread resistance.

Genetic Stutter Can Lead to ALS

Nancy Bonini: Investigator; University of Pennsylvania

Studies that began in yeast and flies led researchers to one of the most common genetic risk factors so far identified for amyotrophic lateral sclerosis (ALS), the devastating neurodegenerative disease also known as Lou Gehrig’s disease. In about 5 percent of patients with ALS, researchers found a genetic stutter that produces too many copies of a short segment of the DNA code in a gene called ataxin-2. That mutation appears to contribute to the protein clumping that interferes with the normal function of motor neurons in people with the disease.

TB Meets Its New Enemy

Bill Jacobs: Investigator; Albert Einstein College of Medicine

Inactivating an enzyme that helps the tuberculosis bacterium convert sugar to another form for energy storage stalls the chemical pathway, killing the microbe with a toxic intermediary that builds up. The metabolic pathway is not present in mammalian cells, or in the beneficial bacteria that live in the gut, making it an attractive drug target. Drugs that inhibit the enzyme could kill the tuberculosis bacteria without harming human cells or digestion, and they could do so with a mechanism that is distinct from existing therapies—important in fighting a pathogen notorious for its ability to develop resistance to a variety of drugs.