Fearless Woman Lacks Key Part of Brain,by Cassandra Willyard on 16 December 2010

"SM" is a bit of an emotional anomaly. The 44-year-old mother, given those initials to preserve her anonymity, isn't scared of snakes. She doesn't shriek when she sees a scary movie. Even haunted houses don't give her chills. SM is pretty much fearless—and now scientists think they've figured out why.

The study's lead authors met SM, who has a rare genetic condition called Urbach-Wiethe disease, more than 2 decades ago. As a result of her illness, she has "two perfectly symmetrical black holes" where her amygdala should be, says Justin Feinstein, a graduate student in clinical psychology at the University of Iowa in Iowa City. The amygdala is a pair of almond-shaped clusters of neurons in the brain that play a role in fear and anxiety. And indeed, when the researchers examined SM, they found that she could not recognize fear on others' faces.

In the new study, the researchers—who now included Feinstein—tested whether SM could experience fear. They took her to a pet store filled with snakes and spiders, showed her clips from horror films (including The Silence of the Lambs and The Shining), and brought her to the annual haunted house at the Waverly Hills Sanatorium in Louisville, Kentucky, a notoriously scary place.

In each situation, SM failed to act fearful. Instead, she seemed excited and curious. In the pet store, for example, she held a snake and rubbed its scales despite telling the researchers that she "hates" snakes. In the haunted house, SM led the way, smiling and laughing. SM didn't report feeling scared. Throughout each experience, the researchers asked her to rate her fear on a scale of 1 to 10. In each case, she selected low values, 2 or lower. But SM isn't an unfeeling robot. She reports experiencing other emotions—surprise, happiness, disgust—and understands that scary movies might induce fear in others.

The researchers also gave SM an electronic diary. Three times each day, the diary displayed a list of 50 questions asking her to rate her current emotional state. The emotion that received the highest average rating during the 3 months SM had the diary was "fearless." She never reported being scared, fearful, or afraid. Similarly, SM's score was much lower than normal on a series of questionnaires aimed at assessing recent fear and how much fear she would feel in a series of hypothetical situations, such as talking to other people or getting lost.

When the researchers delved into SM's past, they found the same fearlessness. The woman says she is scared of snakes, but her son once saw her pick up a large snake and move it off the road. When SM was held at knifepoint in a dark park, she recalls remaining calm and not being scared. As an adult, SM has been the victim of numerous crimes, but the only fearful experiences she could recall happened when she was a child. The researchers posit that the bulk of the damage to SM's amygdala occurred at about the age of 10.

The results suggest that "the amygdala is a critical brain region for triggering a state of fear when an individual encounters threatening stimuli," Feinstein and his co-authors write today in Current Biology. It's the first human study to show that amygdala damage can wipe out fearful feeling, they say. It also contradicts a 2002 paper that showed that patients with damage to one or both halves of the amygdala had no deficit in their ability to feel fear.

The authors point out that the amygdala communicates with other regions of the brain to orchestrate the fear response. "Because SM is missing her amygdala, she doesn't have this cascade of responses that comprise a state of fear," Feinstein says. "And because of that, she's unable to feel fear."

"It's an important observation," says David Anderson, a neurobiologist at the California Institute of Technology in Pasadena who studies the neural circuits involved in fear. But he notes that there's no way to unequivocally prove that SM's responses are the result of damage to her amygdala. "One would like to have more subjects than just one," he says.

Elizabeth Phelps would also like to see evidence in more patients. "I don't believe you can make a general statement about what the amygdala does by a single case study," says the cognitive neuroscientist at New York University and author of the 2002 study that returned opposite results. The authors, she says, were too bold in their conclusions. "The data are mixed."

If confirmed, Feinstein says the findings might lead to new therapies for post-traumatic stress disorder, such as new forms of psychotherapy that hinder the amygdala's activity. Still, fear is an important emotion, notes Anderson. So "you would not want to advocate permanent destruction of the amygdala in soldiers as a way to protect against possible post-traumatic stress disorder," Anderson says.

As for Feinstein's own amygdala, it appears to be intact. "A lot of things scare me, including snakes and spiders," he says. "You couldn't pay me enough money in the world to touch these animals."

Sperm May Hold Cure for Diabetes, by Carrie Arnold on 13 December 2010

PHILADELPHIA, PENNSYLVANIA—Men with type 1 diabetes may one day be able to use the stem cells that become sperm to replace their insulin-producing pancreatic cells. Such transplants would eliminate the need for frequent daily insulin injections to control blood sugar.

Type 1 diabetes occurs when the immune system attacks and destroys insulin-producing islet cells in the pancreas. Without insulin to help cells absorb blood glucose, a person can't use energy from food. Untreated type 1 diabetes is always fatal, but regular insulin injections and blood-sugar monitoring can allow patients to have fairly normal lives.

Occasionally, insulin injections aren't enough to keep type 1 diabetes in check, however. So in the late 1990s, researchers at the University of Alberta in Canada began transplanting islet cells from cadavers into diabetics. This isn't an ideal solution, though, as recipients have to remain on immune-suppressing medication for the rest of their lives to prevent transplant rejection and usually still require some insulin injections.

Stem cell biologist G. Ian Gallicano of Georgetown University in Washington, D.C., and colleagues believe they have found a method that would give diabetics the advantages of islet cell transplantation without the need for immunosuppressant drugs. Millions of sperm cells are created each day from stem cells in the testes known as spermatogonial stem cells (SSCs). The researchers harvested SSCs from human testicular tissue and engineered them to become pluripotent stem cells, which have the capability to specialize into any type of cell, a process that took 2 weeks. Then, the researchers prodded these stem cells to develop into islet cells.

As they reported here yesterday at the annual meeting of the American Society for Cell Biology, Gallicano and colleagues transplanted the engineered human islet cells into diabetic mice that don't have an immune system and so can't attack the inserted cells. The transplants lowered the mice's high blood glucose levels, a good sign that the cells would do the same thing in humans.

Gallicano cautions, however, that the technique isn't ready for people just yet. "We don't get enough insulin from each cell to cure diabetes in humans."

That's a concern echoed by Sheng Ding, a biochemist at The Scripps Research Institute in San Diego, California, who wasn't involved in the research. Before the technique is ready for the clinic, he says, researchers will need to increase insulin production in the transplanted cells. Still, Ding says, "This represents one direction to pursue for ultimately curing type 1 diabetes."

This isn't the first attempt to treat or cure diabetes with stem cells. Researchers had previously used cells from skin or other tissues to create a slightly different type of stem cell, known as an induced pluripotent stem (iPS) cell, which could then go on to replace the damaged islet cells. Using iPS cells does have some advantages, Gallicano says. They don't require an invasive procedure to obtain, and they work for both sexes. However, researchers need to add four genes to morph cells into iPS cells. The genes don't always insert in the right place, which could cause cancer or cell death, he says.

The human SSCs, though, found in men only, are already stem cells and don't need those four genes turned on. "We don't have to do anything to make them pluripotent except take them out of their niche" in the testes, Gallicano says.

The researchers hope that they can find a method that would benefit female diabetics as well. Gallicano says he sees no reason why egg precursor stem cells can't also be used. One major difference is that the egg stem cells have only one copy of every gene, whereas the SSCs have two copies, like other cells in the body, which makes it easier to apply the technique to SSCs.

There's one more hurdle, says Gallicano, which is finding out whether the immune system, which has already created antibodies against the body's islet cells, will attack the transplanted cells as well.