BENCHMARKS
DISCOVERY AT harvard medical school
‘Oligopaints’ allow researchers to probe virtually any sequenced region equencing genomes, from those of simple organisms to those of creatures as complex as humans, produces torrents of information that grow as technical advances push down the cost of generating genetic data. But researchers’ ability to study the chemical nature of DNA has outstripped their ability to actually “see” chromosomes and their position in the nucleus. Yet knowing how chromosomes fold or stretch is critical to understanding gene expression and also has implications for understanding congenital abnormalities as well as cancer. A new tool, called oligopaints, may change the
imbalance between what can be sequenced and what can be seen. By developing renewable, highly specific fluorescent probes that can “paint” the genome, a research team led by Ting Wu, an HMS professor of genetics, has produced a low-cost, high-resolution method for bringing chromosomes to light. The team reported its findings in the December 26, 2012, issue of Proceedings of the National Academy of Sciences. “There have been some fantastic technologies that have given people a molecular handle on how chromosomes are folded— these involve looking at millions of cells at once,” Wu says. “What people are also hankering for is
6 harvard medicine ~ winter 2013
Can You Hear Me Now? hair cells, the fingerlike projections in the inner ear that are so necessary for transmitting sound to the brain for processing and translation, have been regenerated in a mouse model, the first such restoration in an adult mammal. The finding, reported in the January 10 issue of Neuron by HMS researchers at Massachusetts Eye and Ear, holds potential for future therapies that may someday reverse deafness in humans. Hearing loss affects nearly 50 million people in the United States. The most common form, sensorineural hearing loss, is caused by the loss of sensory hair cells in the cochlea or inner ear. Such loss can result from noise exposure, aging, infections, and certain antibiotics and anticancer drugs. Although hearing aids and cochlear implants can ameliorate the symptoms, there are no known treatments to restore hearing because auditory hair cells in mammals do not regenerate. In the experiment, the researchers applied a drug to the cochleas of mice that had lost hearing owing to noise trauma. The drug, known for inhibiting an enzyme called gamma-secretase, had been selected for its ability to generate hair cells when added to stem cells isolated from the ear. When applied, the drug inhibited a signal generated by a protein called Notch on the surface of cells that surround hair cells. Once freed from Notch’s control, the supporting cells developed into new hair cells. —Mary Leach
Brian Beliveau, Eric Joyce, and Nicholas Apostolopoulos (far left); Dr. DAvid Furness/Wellcome Images
Genome Expressionism
the ability to see every nucleus for itself.” Scientists have long used chemical stains to view chromosomes in the nucleus, but such methods did not provide the precision needed to detect the nuclear arrangement and integrity of individual chromosomes. To light up chromosomes, a paint technique called fluorescent in situ hybridization was developed, but it has remained both laborious and expensive. Wu’s lab focused on lowering the cost of painting by employing easily made oligonucleotides, which are short, single-stranded DNA sequences. The probes they developed contain as few as 32 bases, compared to the 100 bases or more of other methods, and can target any sequenced region of the genome along a chromosome. Each oligopaint probe carries singlefluorophore primers, so it lights up at only one point, allowing for greater precision in super-resolution microscopy and image interpretation. One of the goals of Wu’s lab is to make chromosomal analysis as inexpensive as a blood test. Such a test could potentially be used to screen newborns for congenital abnormalities or to guide treatment for cancer patients. The lab has thus far been working in fruit flies and human cell lines, but the principle could apply to any organism, including humans. —Elizabeth Cooney
