Gene therapy helps counter hemophilia B

A gene therapy based on a cargo-toting virus that gravitates to liver cells might provide hemophilia B patients with long-lasting protection against bleeding, an international team of scientists reports online December 10 in the New England Journal of Medicine.
Hemophilia B is the second-most common form of hemophilia, a hereditary disorder in which blood fails to clot properly. Patients must receive preventive injections of a clotting compound called factor IX to prevent bleeding from cuts, scratches or bruises. In the new study, four of six hemophilia B patients given the gene therapy no longer need the clotting compound.
The work “is truly a landmark study, since it is the first to achieve long-term expression of a blood protein at therapeutically relevant levels,” physician Katherine Ponder of Washington University in St. Louis, who wasn’t part of the study team, wrote in the same issue of the journal. The findings were also presented December 11 in San Diego at a meeting of the American Society of Hematology.
British researchers treated six men ages 27 to 64 with the gene therapy, an innocuous virus coupled with components that induce liver cells to make factor IX. Before the study, the men had been getting intravenous infusions of factor IX two to three times a week, says study coauthor Andrew Davidoff, a surgeon at St. Jude Children’s Research Hospital in Memphis, Tenn., where the gene therapy was designed.
Each patient received a single infusion of the therapy, called serotype-8-pseudotyped, self-complementary adenovirus-associated virus vector. Scientists have now monitored the men for nine to 20 months.
Four patients who received medium or high doses of the therapy have made enough factor IX themselves to cease getting the preventive infusions of it. Two patients who were given low doses of the gene therapy are making less. While they still need factor IX infusions, they have cut back to one every 10 to 14 days, Davidoff says.
The virus used as the delivery vehicle, known as AAV-8, was chosen in part because it is unlikely that many people receiving it would have been exposed to it and already made antibodies against it, Davidoff says. The virus also targets liver cells, which naturally make factor IX. And although AAV-8 enters a cell it doesn’t integrate with material in the nucleus, greatly reducing the risk that the therapy would interfere with normal cell function.
Because of these attributes, “there’s a modest level of excitement” about this approach, says hematologist W. Keith Hoots of the National Heart, Lung, and Blood Institute in Bethesda, Md., which funded the study in part. The treatment cannot be repeated in a patient, however, because the immune system would recognize AAV-8 the second time around. Even so, the approach has promise because there are dozens of other AAVs that are still untapped, Hoots says.
Two of the patients were given a brief course of steroid drugs when they showed signs of liver inflammation, but no other side effects emerged. Earlier tests in large animals had shown that this therapy could last 10 years or longer. Further testing in people is planned, Davidoff says.

Eggs have own biological clock Aging mechanisms in worms’ reproductive cells differ compared with rest of body

DENVER — Egg cells age differently than cells in the rest of the body, a new study shows.

The finding, from experiments with roundworms presented December 5 at the annual meeting of the American Society for Cell Biology, might one day lead to ways to predict how long women will stay fertile or even to extend a woman’s fertile years.

Princeton University biologist Coleen Murphy and her colleagues study aging in the roundworm, Caenorhabditis elegans. The worms typically live for about 21 days, but fertility drops off sharply after about a week and the worms can no longer reproduce after they are about 9 days old. Even though 9-day-old worms still have plenty of eggs left, the egg cells, also called oocytes, are of such poor quality they can’t produce embryos.

Women experience a similar sharp decline in fertility starting in their late 30s. This drop-off in reproductive capability is one of the earliest signs of aging.

In earlier work, Murphy and colleagues discovered that certain mutations in biological processes regulated by insulin prolonged worms’ lives and gave them about three extra fertile days. Mutations in a different biological process, controlled by a protein called TGF-beta, extended fertility but not life span.

In the new study, the researchers examined which genes are turned on or off to prolong life and fertility in the oocytes and other body cells of the long-lived worms.

“We were really surprised to find this was a completely different mechanism” controlling aging in eggs compared with other body cells, Murphy said at the cell biology meeting. “In fact, there was almost no overlap between the genes involved in the long life of worms and those that extend fertility in the oocytes.”

Body, or somatic, cells are known to turn on stress-management genes to protect proteins and change metabolism as they age. But oocytes don’t bother with guarding proteins, Murphy and her colleagues found. Instead, eggs ramp up production of factors that protect them from or repair DNA damage and make more of proteins that help egg cells divvy up their chromosomes correctly, the researchers reported.

Because the entire job of an egg is to provide genetic information used to build a new generation, it is perhaps not so surprising that eggs devote resources to making sure the DNA stays healthy and chromosomes and are allocated properly, said Craig Blackstone, a physician and researcher at the National Institute of Neurological Disorders and Stroke in Bethesda, Md. “It makes sense that this would happen, but it hadn’t been shown before,” he said. “It’s clever of her to study this.”

Cilia control eating signal Little hairlike appendages in brain cells control weight by sequestering an appetite hormone

A primary cilium (red) protrudes from a neuron (green). Most normal cells in healthy people have primary cilia. New research shows that the hairlike cilia help suppress appetite.

DENVER — The action of tiny hair-like appendages on cells can mean the difference between fat and thin. Now scientists have a better idea of how the little hairs, called primary cilia, control appetite.

Primary cilia — single, hairlike projections that all cells in vertebrates usually have — seem to sequester a protein that senses and responds to an appetite-stimulating hormone, Nicolas Berbari of the University of Alabama at Birmingham reported December 6 at the annual meeting of the American Society for Cell Biology. In people and mice that lack primary cilia, the appetite stimulant works overtime, leading to overeating and obesity, Berbari said.

These findings may lead to new ways to control appetite and prevent or reverse obesity.

And the study may help scientists better understand the process of eating, said Kirk Mykytyn, a cell biologist at Ohio State University in Columbus. “This work is important because it’s more thoroughly clarifying the molecular mechanism involved in obesity associated with the loss of cilia,” he said.

A mouse that lacks primary cilia in its cells becomes obese (right) compared with a normal mouse (left).

People with Bardet-Biedl syndrome have defects in genes responsible for building primary cilia. A prominent consequence of the disease is obesity. Working with mice that also lack primary cilia due to defects in the same genes, Berbari and his colleagues tried to figure out exactly how the cellular appendages are involved in appetite.

Previous research had suggested that primary cilia work like tiny antennae, helping nerve cells in an eating-control center of the brain to sense an appetite-dampening hormone called leptin. The theory was that taking away the cilia also removed leptin’s ability to put the brakes on eating.

But Berbari and colleagues found that mice lacking cilia still respond to leptin as an appetite suppressant, suggesting that sensing the hormone is not the problem.

“The original work was barking up what was the most obvious tree, but turned out to be the wrong tree,” Berbari said.

Instead, the researchers discovered that a protein called MCHR1, which senses an appetite stimulant called melanin-concentrating hormone, is normally found in primary cilia. Concentrating the sensor protein in the cilia may keep the protein from inappropriately triggering eating.

Berbari has preliminary evidence that his hypothesis may be correct. He fed peanut butter pellets containing a drug that inactivates MCHR1 to mice with intact cilia and to mice that have no cilia. The mice with intact cilia maintained their regular weight despite having unlimited access to food. Mice lacking cilia lost weight when given the drug, suggesting that turning off MCHR1’s ability to stimulate appetite corrects the appetite-control problems caused by missing cilia.

The researchers still don’t know exactly how MCHR1 activity stimulates appetite or how the cilia keep the sensor in check.

Biology’s big bang had a long fuse

A new effort to date the early history of modern animals finds a lot of evolutionary dawdling.

The last common ancestor of all living animals probably arose nearly 800 million years ago, a multidisciplinary research team reports in the Nov. 25 Science. From that common ancestry, various animal lineages diverged and evolved on their own paths. Yet the major animal groups living today didn’t arise until roughly 200 million years later, in an exuberant burst of forms preserved in fossils during what’s called the Cambrian explosion.

“There’s a deeper history that’s been missing from the fossil record,” says study coauthor Kevin Peterson of Dartmouth College. He and his colleagues have been pushing back that date for a last common ancestor, and now, he reports, the analysis has the broadest reach yet. “We show that animals evolved quite a bit before they show up in the fossil record.”

This work updates the notion of a long evolutionary lag, when much of the basic biological toolkit was already in place for a later surge of new body forms, says paleontologist and study coauthor Douglas Erwin of the National Museum of Natural History in Washington, D.C., and the Santa Fe Institute.

“The Cambrian explosion is like the industrial revolution,” Erwin says. Inventions that would later be important for a major shift in technology — or, in this case, genetic novelties important for evolution — appeared long before they played a role in widespread changes that had a major impact on life.

For understanding animal origins, the new paper “is really worthwhile as it stands back and tries to make sense of the whole picture,” says James Valentine of the University of California, Berkeley, who studies animal evolution.

Just what happened with animals during that Cambrian explosion remains one of the more celebrated puzzles in the history of life. Charles Darwin mused over how diverse animal forms appear suddenly (geologically speaking) without much in the way of precursors. Darwin’s answer, as Erwin puts it, was that paleontologists just needed to look harder.

More than a century of hard looking has turned up some signs, fossils as well as traces of biological chemistry, of enigmatic animal life before the Cambrian period began about 541 million years ago. Yet the relationship to modern animals often is not clear. Theories themselves have exuberantly exploded in number and form.

For the new study, Erwin and the rock side of the team updated the scorecard on the earliest fossil occurrences with recent fossil finds and the current thinking on dates of rock layers. On the molecular side, Peterson and his colleagues expanded the family tree to cover seven genes from 118 different kinds of living animals. Fossils provided dates for a scattering of branch points in the tree, allowing researchers to estimate time from rates of change.

Combining fossil dates and the DNA analysis, Peterson, Erwin and their colleagues conclude that the basic genetic tools for fancy animal bodies arose long before a surge of evolutionary innovation around the Cambrian period gave rise to modern animal forms.

During that 200 million-year-plus run-up to the Cambrian explosion, animals did evolve more diverse cell chemistry to regulate basic genes, and the environment changed. But Peterson attributes much of the Cambrian rise of modern animal forms to changes in the interactions among organisms themselves. “You see an evolutionary explosion, if you will, because animals are eating other animals for the first time,” he says.

The paper’s discussion of toolkit genes and the diverse cell chemistry that arose to orchestrate them overlooks some possibly important complexity, objects molecular biologist Mark Q. Martindale of the University of Hawaii’s Kewalo Marine Laboratory. At least 30 percent of the genes of animals analyzed so far have no recognizable similar gene in another species. “These so-called orphan genes could have a tremendous amount to do with diversification of animal lineages, but people just pooh-pooh these differences and focus on the things that are shared,” he says.

Some of the relationships in the evolutionary tree “have been and will continue to be controversial,” says evolutionary biologist Casey Dunn of Brown University in Providence, R.I., who wasn’t involved in the research. “But the point of the tree isn’t the relationships themselves — it is some key dates.”

Neuron transplant in damaged brain fixes obesity

A neuron transplant has rewired damaged brain areas in mice, raising hopes that similar transplants might one day help to treat spinal-cord injuries, Parkinson's disease and other brain conditions.

Jeffrey Macklis at Harvard University and his colleagues took healthy neurons from mouse embryos that had been labelled with a green fluorescent protein. They used them to repair a brain circuit involved in the regulation of food intake and body weight in response to a hormone called leptin in mutant mice born with damage to that area, which become dangerously overweight as a result.

The fluorescent neurons survived the transplant, integrated into the brain circuit, and differentiated into mature neurons that could communicate with existing neurons and respond to leptin, insulin and glucose – suggesting that they had repaired the damaged circuit. The treated obese mice went on to weigh 30 per cent less than their untreated counterparts.

"These embryonic neurons were wired in with less precision than one might think, but that didn't seem to matter," says Jeffrey Flier, dean of Harvard Medical School, who was part of the team. "They are like antennas that were immediately able to pick up the leptin signal."

The next question is whether transplanted neurons could rewire other complex brain circuits involved in diseases or brain injury, which might be more dependent on signals coming from other neurons, rather than signals coming from the blood. "In these cases, can we rebuild circuitry in the mammalian brain? I suspect that we can," says Macklis.

Journal reference: Science, DOI: 10.1126/science.1209870

Exceptional memory linked to bulked-up parts of brain.....People who can recall life’s events in detail have enlarged region linked to obsessive-compulsive disorder

WASHINGTON — Like the fictional detective Carrie Wells on the TV show Unforgettable, some real-life people can remember every day of their lives in detail. Those superrememberers have more bulk in certain parts of their brains, possibly explaining the remarkable ability to recall minutiae from decades ago, researchers said November 13 at the annual meeting of the Society for Neuroscience.

One brain region involved in such incredible recall has been implicated in obsessive-compulsive disorder, hinting that OCD and superior memory might have a common architecture in the brain.

Scientists have long studied people with memory deficits, but there haven’t been many studies on people with exceptional memories. “Looking at memory from a deficit gave us a lot of insight into memory,” said study coauthor Aurora LePort of the University of California, Irvine. “Looking at memory from a superior perspective gives us a new tool. It may just broaden our knowledge and ability to know what’s going on.”

In 2006, UC Irvine neuroscientist Larry Cahill and collaborators published a report on a woman who could remember detailed accounts of her life. Cahill and colleagues then began hearing from many people who claimed to have extraordinary memories. After sifting through and eliminating the impostors, the team was left with 11 people who scored off the charts for autobiographical memory. These people could effortlessly remember, for instance, what they were doing on November 2, 1989, and could also tell you that it was a Thursday. “They’re not going home and saying ‘OK, let me write down what I did today and memorize it,’ ” LePort said.

Using brain scans, researchers found that people with supermemories had larger brain regions associated with memory, including the left temporoparietal junction and the left posterior insula. What’s more, a brain structure called the lentiform nucleus, a cone-shaped mass in the core of the brain, was bigger in people with exceptional memories. This brain area has been linked to obsessive-compulsive disorder.

The subjects haven’t been clinically evaluated for OCD, but LePort says that there are some similarities. “The ability to organize their memories by dates seems to relieve anxiety,” she says.

Researchers don’t know how the brain accomplishes this feat. These people could encode information more effectively, or have a better system of retrieving it, or both. “Right now, we can see the brain areas that are coming out and speculate about what’s going on,” LePort says.

The team hopes to do further studies examining what’s happening in the brain as these people remember.

One tantalizing lead suggests that genetics might be involved. Though no genetic tests have been performed, some of the volunteers have reported that family members share extraordinary powers of recall, LePort says.

The result “certainly pushes us beyond the boundaries of what we might normally think,” said memory expert Howard Eichenbaum of Boston University. “It violates a standard principle that most of us have, which is that normal memory is pretty damn optimized.”

The volunteers are now keeping detailed diaries, so that the scientists can test whether particular kinds of memories are better suited to recollection. People might be better at remembering emotional memories, for instance.

Radiation sickness treatment shows promise

A drug composed of an ordinary antibiotic combined with a microbe-fighting compound may be enough to protect thousands of people from the ravages of radiation sickness in the aftermath of a major nuclear accident or attack, experiments with mice suggest.

Researchers exposed mice to a heavy dose of radiation and 24 hours later gave some of them injections of an antibiotic and a protein that’s made naturally by the immune system. Thirty days later, most mice that received no treatment were dead, whereas nearly 80 percent of mice that received the treatment still appeared healthy, a team reports in the Nov. 23 Science Translational Medicine.

Follow-up studies are still needed before the combo can be used to treat people, but versions of the antibiotic and the protein have already been used in humans, so the new approach looks promising. It might even be used as a preemptive measure for first responders.

“This could potentially be very useful,” says radiobiologist Gayle Woloschak of Northwestern University in Chicago, who was not involved with the study.

Radiation exposure of levels up to 10 gray (the mice received 7 gray, about 45,000 times the dose of a chest X-ray) would usually require a bone marrow transplant and probably treatment with a compound that stimulates bone marrow growth. “During a mass casualty event you’re not going to be able to do bone marrow transplants,” says Woloschak. And while questions remain about long-term survival of mice given the new treatment, “it’s quite exciting,” she says.

When the body is exposed to intense levels of radiation, bone marrow is one of the first things to shut down. Bone marrow is where most white blood cells arise, so the body’s immune system can’t fight infection properly when compromised. And a working, fighting immune system is just what’s needed after exposure to radiation. Radiation can cause bacteria that are usually confined to the gut to leak into the blood, causing blood pressure to spike, fever, abnormal blood clotting and even organ failure.

The new treatment goes after these marauding bacteria. The fluoroquinolone antibiotic, a mouse version of Cipro, aims to kill any bacteria it comes across. And the protein, called BPI, mops up and latches onto bacterial endotoxin, a nasty molecule on the coats of many bacteria.

“We think we have a combination here that is multifunctional,” says stem cell transplant doctor Eva Guinan of the Dana-Farber Cancer Institute and Harvard Medical School, who led the work with Ofer Levy, also of Harvard and Children’s Hospital Boston. “We still have a lot more to explore in detail, but the results are really encouraging.”