Research rundown

Four recent findings from Children’s labs offer new insight into some of today’s most newsworthy ailments.

SARS Interrupted

Last year, SARS, or severe acute respiratory syndrome, had people from Beijing to Boston cringing at every sneeze or cough around them. Now researchers from Children's, Brigham and Women¡s Hospital, and UMass Medical School are working hard to find a solution to the deadly disease.

The SARS virus enters the body through a receptor on the cell surface, which acts as a "lock.” The researchers found not only the lock, but the "key”—a protein on the virus that attaches to the receptor. They were able to plug up this lock with antibodies against the receptor, preventing the viral protein from attaching to the cell surface. In theory at least, this should also block the SARS virus from causing infection.

Children's investigator Hyeryun Choe, PhD, cautions that this work is just a first step in controlling SARS. "We need to investigate whether the virus' use of this receptor contributes to the severity of the disease,” she says, "and whether the virus produces other molecules that make SARS deadly” (Nature, Nov. 27, 2003).

 

Viral Strategies Take Shape

Three-dimensional visual images of the tropical dengue virus offer clues to how a whole class of viruses – including West Nile, hepatitis C and tick-borne encephalitis – enter cells and cause disease. Featured in a recent Nature cover article, the images also suggest new strategies for blocking these infectious diseases with drugs.

Stephen Harrison, PhD, chief of Molecular Medicine at Children’s and a Howard Hughes Medical Institute investigator, notes that many of the viruses in this family, including West Nile and dengue itself, are making their first appearances in the U.S. “One of the ways we can be forearmed is understanding the mechanism of viral entry,” he says. The research focused on the little-understood final step of viral entry: fusion of the virus’ outer membrane, or envelope, with the membrane of the cell being attacked. Fusion allows the virus to release its genes inside the cell, so it can reproduce and infection can spread.

Led by structural biologist Yorgo Modis, PhD, a postdoctoral fellow in Harrison’s lab, the team aimed an X-ray beam through a key protein in the dengue virus’s envelope. Images of the protein in crystallized form revealed how it changes shape so that fusion can happen. “The protein folds in half; jackknifes on itself,” Modis explains. “This forces the cell membranes together, causing them to fuse.” He and Harrison hold a provisional patent on two treatment strategies that would use drugs to block shape change (Nature, Jan. 22, 2004).

 

Germ Cells and Primitive Sperm Grown in the Lab

Infertile couples and others may benefit from research cited by Science magazine as one of the Top 10 Breakthroughs of 2003. Children’s stem cell biologist George Daley, MD, PhD and collaborator Niels Geijsen, PhD, took two unprecedented steps: first, working with mice, they created a continuously growing line of embryonic germ cells – primitive cells that mature into sperm or eggs – providing a ready supply of cells that are notoriously hard to isolate. Next, they allowed these germ cells to mature into primitive sperm. Although these sperm cells weren’t fully fledged (they lacked tails, for instance), they successfully fertilized mouse eggs in the laboratory, creating early embryos with full sets of chromosomes. The next step will be to transfer these early embryos into females to see if they develop into healthy baby mice.

If more germ cells could be coaxed into maturing into sperm, men who can’t make viable sperm on their own might be able to father children. A better understanding of germ-cell maturation might also shed light on birth defects. Also, since embryonic germ cells retain the capacity to generate all kinds of tissues, they will help scientists study the process of cell specialization and, perhaps, how to “reprogram” adult cells to create tissues needed by the body (Nature, Jan. 8, 2004).

 

A Gene for Long Life

Just one in 10,000 Americans lives to be 100. Work that started in the lab of Louis Kunkel, PhD, director of the Children’s Genomics program, has flagged a single gene that may separate these hardy souls from the rest of the pack.

Kunkel’s lab began by scanning the genomes of pairs of exceptionally long-lived siblings (aged 100 – or nearly 100). The search found a strong link between longer lifespan and a region on chromosome 4 containing some 50 genes. Children’s and Beth Israel Deaconess Medical Center recently won a patent for this work, which they licensed to Elixir Pharmaceuticals.

Kunkel, a Howard Hughes Medical Institute investigator, stayed on as advisor as Elixir carried on the search, looking for a specific gene on chromosome 4 that might hold the secret of long life. This search turned up a gene, known as microsomal transfer protein (MTP), which may extend lifespan by controlling the production of “bad” cholesterol. This allows people to dodge diseases like stroke, coronary artery disease and other vascular maladies. The search is on for drugs that do what MTP does naturally (Proceedings of the National Academy of Sciences, Nov. 10, 2003).