Genetic discoveries chip away at autism

From left, Yiping Shen, PhD, David Miller, MD, PhD, and Bai-Lin Wu, PhD

Children's Hospital Boston is beginning to crack the intricate genetic code of autism. As members of the Boston-wide Autism Consortium and through independent research, Children's researchers have confirmed that a section of chromosome 16 is deleted or duplicated in some people with autism spectrum disorders (ASDs). These findings, discovered through the largest, most complete whole-genome study conducted to date, were published online by the New England Journal of Medicine in January.

The consortium tested more than 3,000 DNA samples from a national repository, including 1,441 people with some form of ASD, and identified five with chromosome 16 deletions. An independent team from Children's Genetics Diagnostic Laboratory tested 512 patients with developmental delay and/or suspected ASDs and found an additional five cases. Extending the findings, they also found four patients with a duplication of the same region.

"We are particularly gratified to have jumped the gap between research observations and the diagnostic testing we offer to patients," says laboratory Director Bai-Lin Wu, PhD, leader of the Children's team. A clinical test for the deletion/duplication is now available through the laboratory.

"The ability to reliably find extremely small missing or extra pieces of DNA has evolved just within the last six to eight months," notes coauthor Yiping Shen, PhD, director of Research and Development at the laboratory.

The defect accounts for an estimated 1 percent of autism cases, adding to the roughly 15 percent of ASDs with known genetic causes, says David Miller, MD, PhD, the lab's assistant director. "I don't think we'll find one cause that explains 50 percent of autism," Miller says. "But even if it's 1 percent at a time, we'll eventually be able to figure out what's going on in each family."’ÄØ

Melanoma: going for the jugular

A colony of malignant melanoma cells grown from a single melanoma stem cell.

It's increasingly believed among scientists that nearly every cancer contains small populations of highly dangerous cells—cancer stem cells—that can initiate a cancer, drive its progression and create endless copies of themselves. Going on the theory that targeting these cells might be an effective therapeutic strategy, researchers around the world have begun isolating stem cells from various kinds of cancers. Now, for the first time, researchers at Children's Hospital Boston and Brigham and Women's Hospital (BWH) have found a strategy that selectively targets cancer stem cells for destruction, successfully halting one of the deadliest cancers—melanoma—in mice. They reported their findings in the January 17 issue of Nature.

The percentage of people who develop melanoma in the United States has more than doubled in the past 30 years. It usually grows initially as a flat brown to black spot that can be removed surgically if recognized early, but once a three-dimensional nodule develops, it gains the ability to move to other parts of the body and becomes deadly. Markus Frank, MD, and Tobias Schatton, PharmD, of the joint Children's-BWH Transplantation Research Center, in collaboration with pathologist George Murphy, MD, of BWH, isolated melanoma stem cells and found that they have, on their surface, a special protein that helps shuttle toxic agents out of the cell. Previously, Frank and Natasha Frank, MD, (also in Children's Division of Genetics), discovered and cloned this protein, known as ABCB5, and showed that it enables these cancerous cells to avoid being killed by chemotherapy drugs. Now, they show that ABCB5 is unique to the subpopulation of melanoma stem cells.

But most strikingly, Frank and colleagues were able to leverage ABCB5—normally a protector—to outsmart and bring about the destruction of these highly virulent stem cells in mice bearing human melanomas. They injected the mice with custom-made antibodies that bound only to the cells with the ABCB5 protein (melanoma stem cells). The antibodies stimulated an immune response that led to cell death and significantly inhibited melanoma growth as compared with untreated mice. "This study adds credence to the hypothesis that stem cells drive cancer progression, and lays the groundwork for a possible treatment," says Frank.