In the image below, researchers at Children's Hospital Boston have, for the first time, captured the electrical activity of a single sperm cell. The technically difficult maneuver, reported in the February 9 Nature, also enabled them to pin down the role of a protein vital for male fertility—and establish it as a target for developing a male contraceptive.
A calcium channel CatSper was discovered in 2001 in the lab of Children's researcher and Howard Hughes Medical Institute investigator David Clapham, MD, PhD. Mice that lacked CatSper were completely infertile—their sperm were weak swimmers, unable to penetrate the egg's protective barriers. But no one was sure what role, if any, CatSper played.
Now, Yuriy Kirichok, PhD, and Betsy Navarro, PhD, in Clapham's lab show that CatSper is a key channel by which calcium enters the sperm's tail. The flow of calcium across the sperm's outer membrane, measurable as an electrical current, turbocharges the tail's motor proteins, giving the sperm a last-minute boost. In mice that lacked CatSper, no such current was detectable.
Hydra Biosciences, a biotech company co-founded by Clapham, is pursuing a male contraceptive that would block CatSper without blocking calcium channels elsewhere in the body.
"Before, no one knew what the exact target was," says Navarro. "Now, people can directly test for something that blocks the current."
Children with serious congenital heart defects are typically urged
to restrict their activity, but a study in the December Pediatrics, led by Children's Hospital Boston cardiologist Jonathan Rhodes, MD, indicates that most of these children can benefit from cardiac rehabilitation.
Sixteen children, ages 8 to 17, completed a 12-week program of stretching, aerobics and light weight/resistance exercises. All had serious congenital heart disease and reduced cardiac function on exercise tests, but none had findings that might raise a safety concern, such as arrhythmias or chest pain.
The twice-weekly sessions were tailored to the children's interests and included dance, calisthenics, kick boxing and jump rope. Music, games, balls, relay races and prizes helped keep the kids motivated.
Heart rate was checked initially and two to three times during each session. At the program's end, 15 children showed significant improvements: their hearts pumped more blood with each beat and their muscles used more oxygen. There were no adverse effects.
Follow-up testing found sustained cardiac benefits, whereas non-participating children had a slight decline in cardiac function.
"With the approval of a pediatric cardiologist, and after careful testing, exercise is generally safe and tolerable for children with congenital heart defects," Rhodes says. "A lot of our kids were timid in the beginning, but being with other kids who had never exercised helped melt away their anxiety."
The approach of starving tumors of their blood supply, pioneered by Children's Hospital Boston's Judah Folkman, MD (see Rising star on page 4), has received another boost from biotechnology company Genentech, Inc. Two years ago, Genentech's drug Avastin became the first FDA-approved cancer treatment to specifically target angiogenesis, or blood vessel growth. Now, Children's has granted Genentech an exclusive license to anti-cancer technologies developed in the lab of Vascular Biology researcher Michael Klagsbrun, PhD.
These technologies, involving a cell receptor called neuropilin, share a similar mechanism of action with Avastin. Avastin curbs tumors by blocking a key stimulator of blood-vessel growth—vascular endothelial growth factor, or VEGF—from attaching to VEGF receptors on nearby blood vessels. It is currently approved for use in combination with chemotherapy in patients with first-line metastatic colorectal cancer, and is being tested in a variety of other cancers.
Back in 1998, Klagsbrun and colleagues reported in the journal Cell that VEGF binds not only to the VEGF receptor, but also to neuropilin, a co-receptor originally known for its role in guiding growing nerve fibers to their appropriate destinations. Further studies showed that neuropilin acts with the VEGF receptor to enhance VEGF signaling and function. This made neuropilin a good target for trying to inhibit cancer growth, and several animal studies run by Klagsbrun's team show promise in hitting that target.
Recently, Klagsbrun's lab showed that other agents involved in nerve guidance, semaphorins, are potent angiogenesis inhibitors. The team is now seeking a small version of one of the semaphorins appropriate for commercial development. "It's interesting that something that keeps nerve cells from running around could be a powerful anti-angiogenic agent," Klagsbrun says.
A growing body of research is showing that fetal and newborn brains are biochemically different from the brains of adults, making them more susceptible to seizures and other forms of neurologic injury. Effective treatments are sorely needed as more premature babies survive, but neurologic drugs made for adults often don't work in these tiny babies.
Children's Hospital Boston neurologist Frances Jensen, MD, is discovering molecular pathways unique to the fetal and neonatal brain, and is finding therapeutic promise in drugs that target those pathways. And because some of these agents are already FDA-approved for other uses, clinical trials could begin in the relatively near future.
Jensen's most recent work, published in the November Nature Medicine, finds that an existing, FDA-approved diuretic may suppress seizures in newborns, who respond poorly to conventional anticonvulsants. This study, done with the University of Colorado, found that the poor response is due to high concentrations of chloride in newborns' brains, caused by high levels of a molecule that transports chloride into brain cells. By using the diuretic bumetanide to block the transporter, the researchers were able to suppress seizures in baby rats.
Similarly, in 2004, Jensen reported that topiramate, another existing drug that targets molecules unique to the neonatal brain, may help prevent epilepsy in children who have seizures as newborns. It may also protect newborns against periventricular leukomalacia, a form of brain damage that can lead to cerebral palsy.
"As we learn more about age-specific brain mechanisms, we can develop novel therapies, but in the meantime, there may already be things on the shelf that we can use," Jensen says.
About 5 percent of mammals' genetic makeup has remained virtually unchanged by evolution. Interestingly, genes that code for proteins make up less than a third of these "conserved" portions of the genome. The rest, known as conserved noncoding sequences (CNCs), are increasingly suspected to contain important elements whose variation may contribute to human disease.
Seeking to prove this suspicion, Children's Hospital Boston researchers led by Joel Hirschhorn, MD, PhD, combined a list of CNCs with the recently released HapMap database and the chimpanzee genome sequence. The HapMap project catalogued places where people's genomes vary and measured how prevalent each variant is in the population. By comparing these data with the chimpanzee genome, the researchers identified which variants were new mutations—appearing in humans, but not in chimps. They then compared the pattern of new mutations in the CNCs to that in the rest of the genome.
"There are two possible explanations for genetic regions that haven't diverged much with evolution," Hirschhorn explains. "One is that there are 'cold spots' where DNA doesn't mutate as quickly. The other is that mutations happen as frequently as they do elsewhere in the genome, but that they're harmful and are wiped out by evolution."
Hirschhorn's team reasoned that if the CNCs had a preponderance of mutations that are rare in the population, that would indicate that some of them were harmful, making carriers less likely to pass them on to children. And that is what their computational analysis showed, providing the most direct evidence to date that CNCs perform important functions in the genome.
The study, a collaboration with the Sanger Institute in England, appeared in the December 25 online edition of Nature Genetics.
