'Brains in a dish' guide autism sleuths seeking first medicines

Scientists have found a way to peer into the brains of people with autism: Grow them in a dish.

Aided by stem cell technology that earned Japanese researcher Shinya Yamanaka the Nobel Prize in Medicine three years ago, companies including Novartis, Roche Holding and Johnson & Johnson are gaining new insights into the triggers of a social disorder that afflicts one in 68 people.

The technique known as induced pluripotency has spurred drugmakers to fund a quest for treatments, a sea change for a disease previously viewed as too elusive to tackle.

Thanks to Yamanaka, scientists can now harvest skin samples from the inner arms and legs of patients and grow them into small pieces of brain-like tissue, allowing them to study how genetic mutations affect brain behavior and gauge the response to drugs.

"The first mover in this space is really going to transform the company that gets it," said Rob Ring, the former head of Pfizer's now-disbanded autism research unit. "It's worth the shot."

Roche, the most advanced in the field, is working with the Harvard Stem Cell Institute and Harvard Medical School to test new drugs for autism using the "brains in a dish." The Basel, Switzerland-based company is separately testing an experimental drug called RG7314 in 225 autistic men, with results expected by the end of next year.

At King's College London, scientists are using brain cells developed from skin to study the so-called excitation-inhibition balance, a chemical equilibrium in the brain that may contribute to autism when disrupted.

"It's kind of like the accelerator and brake of your brain," said Declan Murphy, a professor of psychiatry and brain maturation at King's College who is leading the research. There's early evidence that scientists can influence that balance and thereby impact brain functions, he said.

In a study starting later this year that is based on insights gained from the technology, Murphy and colleagues plan to test a drug approved for other neurological disorders in people with autism, after an earlier study in 15 adults suggested it may be able to alter behavior. The college is also working with Roche, J& J, Eli Lilly & Co. and others to develop medicines.

"We used to blame the parents for having autistic children," Murphy said. "It's a huge leap in our understanding that actually this is a biologically based disorder."

There are no approved treatments designed for autism, although two antipsychotics - J&J's Risperdal and Bristol-Myers Squibb Co.'s Abilify - are approved to treat symptoms such as irritability.

A crucial barrier to research was that scientists couldn't take samples from patients' brains in the same way they could collect biopsies from other organs or tumors. Yamanaka's technology, which sidesteps the ethical concerns associated with using embryonic stem cells, changed that.

"You make the assumption that the defect you see in the cells that you make in the lab is similar to the defect that arises in somebody's brain, and you can then use this simplified system to test hundreds of drugs," said Ricardo Dolmetsch, the head of neuroscience research at Novartis.

Dolmetsch, whose 13-year-old son is autistic, says the drugmaker is using the "brain in a dish" approach to delve into the genetic mutations associated with other brain disorders as well, such as schizophrenia and epilepsy. Novartis aims to start human trials in one of those areas as early as next year, though Dolmetsch wouldn't say which one.

"The unmet need is gigantic because there are really zero treatments," he said. "Frankly the way that we have treated it as a society, which is this idea that we try education and when it doesn't work we institutionalize people - it's just not good enough."

Murphy of King's College is helping to lead EU-AIMS, a 32 million-euro ($36 million) five-year project aimed at developing drugs - the largest single grant for autism.

While drugmakers don't disclose how much they devote to autism research, the U.S. National Institutes of Health is spending $190 million this year, a sum split between 480 different grants whose topics range from anxiety management to better ways of measuring treatment outcomes. Two decades ago, the amount the NIH allocated to autism research was $11 million, according to Ring, now chief science officer at New York-based Autism Speaks.

The advocacy organization last month partnered with Google Inc. to launch an online database that by early next year will contain the complete genomes of 10,000 people with autism and their families, more than for cancer or diabetes.

"We're making that a resource for pharma, for the entire field to just go in and get unprecedented access to data," Ring said. "When it comes to understanding autism, all roads lead to the genome."