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Fish-Bowl Neuroscience

A recently hatched zebrafish is swimming upriver for the first time. Its big round eyes, bulging on the front of its eyelash-sized body, scan the surroundings. Suddenly, it sees the scenery flying forwards as a gentle current pushes it backwards. The fish flicks its tail to try to stay in place. Or so it thinks.

In reality, the baby fish is paralysed and suspended in a water-filled Petri dish by glass pipettes. The dish sits on the stage of a US$100,000 microscope in the corner of a darkened, cluttered laboratory. A film, projected from below, has transported the fish to a virtual world in which moving bands of light and dark simulate passing underwater scenery.

Although the fish doesn’t move, the motor neurons that control its tail are firing away, just as if it were swimming. And when fed into a computer, those signals can control the video display, giving the fish nearly every sign that it is swimming normally. All the while, Florian Engert’s microscope peers deep into the fish’s tiny, translucent brain to watch neurons glow green as they fire.

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Nature, January 2013.

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The Aging Microbiome

Almost everything about eating gets more difficult with age. Elderly people typically cannot taste or smell as well as they used to, decreasing the appeal of some foods. Dental issues or a dry mouth can impede chewing; loss of muscle tone in the pharynx can make swallowing difficult; constipation and the side effects of medication can make digestion uncomfortable; and decreased mobility makes a chore of grocery shopping or cooking complex meals. Little wonder that older people eat an increasingly narrow range of foods. But can this, in itself, adversely affect health?

Recent research shows that diet influences the composition of the gut microbiome — the bacterial community in our intestines — in the elderly. In July, a group of researchers, mostly based in Ireland, published the largest study so far of the microbiome in an elderly population. The data indicate that the frailest older people tend to harbour similar intestinal microbial communities. More provocatively, the study also suggests that this microbial make-up is driven by a diet high in fat and lacking in fibre, and that a decline in our microbial community underlies ill health as we grow old.

The conclusion is controversial, as many scientists say these associations can go the other way. An individual’s health, and thus the state of his or her immune system, can also affect the gut microbiota and drive eating habits.

One thing on which everyone agrees, how- ever, is the value of finding out how to alter the microbiome in our favour. “The potential is enormous, especially the idea of figuring out what diet is right for individuals,” says Rob Knight, a microbiome expert at the University of Colorado in Boulder, who was not involved in the new study. “We just don’t have a very good idea yet of the specific parameters that could set the microbiota in a good direction versus a bad direction.”

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Nature, December 2012.

Re-Awakenings

Anna Sumner’s craving for sleep began when she was an 18-year-old high school senior. She thought nothing of it.

When it followed her to college, she blamed it on stress. She was working so hard, she told herself, her body just needed the extra rest. But it was more than that. She would chose naps over eating lunch, working out, or being with friends. Every night after dinner, she came back to her dorm room to sleep. If her parents called on those evenings, her roommate would cover for her, telling them she had gone to the library.

After graduation, Sumner moved to Bangkok to teach English. Her sleeping continued, and so did her rationalizations. It was OK that she was napping between every class because she was adjusting to a warm climate. Then she spent a winter working in London. There, her excuse was the dark and dreary sky.
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Complex Disorder

Defining ‘autism’, a single word encompassing a wide spectrum of behaviours, is no easy task.

Each person with autism has a different combination of symptoms, and the combination may change over that person’s lifetime. Some people with autism don’t speak at all, whereas others are fluent. Some are bothered by sounds, whereas others are musical prodigies. Some are intellectually disabled, whereas others are savants. No wonder then that many researchers have begun referring instead to ‘autisms’.

It has become clear over the past few years that the biology underlying autism is similarly multifarious, with hundreds of potential genetic, developmental and environmental causes.

Still, researchers are on the hunt for a biological signature of autism, one they say is the unmistakable core — a distinctive mix of social disinterest and repetitive behaviours — that marks every individual with the disorder.

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Nature, October 2012.

The Roots of Resilience

On a chilly, January night in 1986, Elizabeth Ebaugh carried a bag of groceries across the quiet car park of a shopping plaza in the suburbs of Washington DC. She got into her car and tossed the bag onto the empty passenger seat. But as she tried to close the door, she found it blocked by a slight, unkempt man with a big knife. He forced her to slide over and took her place behind the wheel.

The man drove aimlessly along country roads, ranting about his girlfriend’s infidelity and the time he had spent in jail. Ebaugh, a psychotherapist who was 30 years old at the time, used her training to try to calm the man and negotiate her freedom. But after several hours and a few stops, he took her to a motel, watched a pornographic film and raped her. Then he forced her back into the car.

She pleaded with him to let her go, and he said that he would. So when he stopped on a bridge at around 2 a.m. and told her to get out, she thought she was free. Then he motioned for her to jump. “That’s the time where my system, I think, just lost it,” Ebaugh recalls. Succumbing to the terror and exhaustion of the night, she fainted.

Ebaugh awoke in freefall. The man had thrown her, limp and handcuffed, off the bridge four storeys above a river reservoir. When she hit the frigid water, she turned onto her back and started kicking. “At that point, there was no part of me that thought I wasn’t going to make it,” she says.

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Nature, October 2012.

Where There’s Smoke

A visitor to China may well notice the country’s smog problem as the plane descends. Smog levels in large cities such as Beijing and Shanghai frequently dwarf those of other metropolitan centres. Then there’s the cigarette smoke. China, the world’s most populous country, claims about one-third of the world’s smokers — at least 300 million people — who collectively puff 1.7 trillion cigarettes a year. In rural areas, cigarette smoke permeates buses, shops and even doctors’ offices.

Beyond cigarette smoke and outdoor air pollution, hundreds of millions of Chinese people breathe unclean air while working in factories and on industrial-scale farms or while cooking at wood-burning stoves inside their homes.

These airborne toxicants — many of which are by-products of China’s economic boom — are risk factors for chronic obstructive pulmonary disease (COPD), an incurable respiratory disorder that can cause severe breathing difficulties. And they have public-health officials worldwide worried about a coming epidemic. “We’re just seeing the tip of the iceberg on COPD in China,” says Don Sin, a respiratory medicine specialist at the University of British Columbia in Vancouver, Canada, who researches COPD. “In 30 years, [the number of cases] is going to explode.”

A large-scale study in China put the prevalence of COPD in 2004 at roughly 8% in people who are 40 or older1, in line with rates in the United Kingdom and the United States. But because China has seen soaring rates of industrialization and tobacco use over the past few decades, and because COPD symptoms aren’t typically noticed until after age 50, public-health experts say the future is bleak. According to Sin, projections based on current trends and World Health Organization estimates show that by 2030, COPD will kill 3 million Chinese people a year — a million more than die annually now.

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Nature, September 2012.

Microglia: The Constant Gardeners

The work required the mind of an engineer and the hands of a surgeon. Axel Nimmerjahn had both.

It was 2002 when Nimmerjahn, then a graduate student at the Max Planck Institute for Medical Research in Heidelberg, Germany, began trying to spy on the everyday activity of the mysterious brain cells known as microglia. Others had caught glimpses of the cells in their spider-like resting state, but only in slices of dead tissue. No one had been able to see them in a live brain. That’s because microglia — which, unlike other cells in the brain, are part of the immune system — are extremely sensitive. Cut a nerve, or release infectious bacteria into brain tissue, and microglia spring into action, retracting their many appendages and morphing into big, round blobs that gobble up pathogens and clear away cellular wreckage.

To see the cells without disturbing them, Nimmerjahn used a newly published approach for imaging a live mouse brain. After anaesthetizing the animal and peeling back its scalp, he removed the top two-thirds of the skull’s thickness and shaved the bone down to just 20 micrometres — thin enough for light to penetrate, but thick enough to avoid setting off the microglia. The work progressed slowly — Nimmerjahn had to douse the surgical site with cooling fluid after realizing that even the heat from scraping could aggravate the cells. But within a few months at the bench, he was able to record some time-lapse movies.

He was floored by what he saw: ‘resting’ microglia are anything but. Their delicate branches snake through densely packed brain tissue, constantly extending and shrinking and re-growing. “They’re very dynamic, much more than any other cell in the adult brain,” says Nimmerjahn, now a biophysicist at the Salk Institute in La Jolla, California. He calculated that the cells’ concerted movements could survey the entire brain every couple of hours. But it was unclear why the microglia were moving so much, Nimmerjahn says. “Why does the brain invest so much energy?”

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Nature, May 2012.

Ovary Banks: Freezing the Biological Clock

The clock started ticking for T. Wilson in 2008, when she turned 36. She had been divorced for seven years, and as a trainee surgeon she barely had time to sleep, let alone date. But her waning fertility was not interested in reasons for putting off a pregnancy. Faced with the possibility that she might never be a mother, Wilson was afraid.

She wanted to preserve her fertility but didn’t like what technology had to offer. At that point, the preferred option for thousands of women all over the world was to freeze their eggs, but Wilson was daunted by the prospect of hormone injections, high cost and the time off work. Then she consulted Sherman Silber, a surgeon in St Louis, Missouri, who suggested she might like to bank one of her ovaries.

It is a highly experimental option.

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New Scientist, April 2012.

MS Genomics: A Complex Code

In spring 2007, half-a-dozen scientists huddled around a laptop at a pub in Cambridge in the United Kingdom, to see the preliminary results from the largest ever genetic study of multiple sclerosis (MS). Expectations were high. Three decades had passed since the last genes were discovered to have a link to MS, in a large genomic region called the major histocompatibility complex (MHC).

Using the pub’s wireless Internet connection, one of the researchers eagerly downloaded the first batch of data. It was disappointing: the analysis found no gene variants outside the MHC that were associated with MS. “We thought, all this work and once again MS eludes us,” recalls David Hafler, one of the leaders of the International Multiple Sclerosis Genetics Consortium (IMSGC).

The next morning, when the researchers convened again at the University of Cambridge, they were in for a pleasant surprise. “The guy who had downloaded the data said: ‘Oh, I made a mistake’,” recalls Hafler, who is now head of neurology at Yale University. When the analysis was done again, the program identified variants near two genes that play an important role in the workings of immune cells.

The report included data from almost 4,000 people with MS. In August 2011, the consortium published an even bigger association study. After screening the genomes of nearly 10,000 people with MS, the group found dozens of genetic variants significantly associated with the disease. An intriguing proportion of these variants fall near genes related to the immune system, bolstering the notion that MS is fundamentally an auto-immune disease that leads to brain degeneration, rather than the other way round. “This disease has an astonishingly immunological flavour,” says Alastair Compston, head of clinical neurosciences at the University of Cambridge and another founding member of the IMSGC.

The hope, Compston says, is that studying these variants will point researchers towards shared biological pathways that would make good targets for drugs.

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Nature, April 2012.