Here's a major stumbling block in developing therapies for human diseases -- it's hard to find a fix if you don't really know what's wrong. Take autism spectrum disorders. By now doctors are pretty good at identifying signs of the disease, but without access to brain cells researchers don't really know what's going wrong.
That's the hurdle that our grantee Ricardo Dolmetsch at Stanford University took on with his Tools and Technologies award. Dolmetsch has a personal stake in this research -- he has a son with the disease.
Dolmetsch proposed taking skin samples from people with forms of autism, converting them to embryonic-like reprogrammed stem cells (so-called iPS cells), then maturing those cells into neurons. Here's the magic: because those cells contain the same DNA mutations as the person who donated the skin sample, the neurons he develops in the lab dish will have the same genetic propensity for autism as those people.
Sure enough, two years ago he published the first results of this work, using cells from people with a condition called Timothy syndrome. People with this syndrome have a high risk of developing autism. In that work, the neurons behaved differently in the lab dish, and he found a possible drug that seemed to reverse those symptoms. (We wrote about that work here.)
Now, he's done similar work in another syndrome called Phelan–McDermid syndrome (PMDS) and published the results in Nature October 16. Again, he got skin cells from people with this syndrome, reprogrammed them into iPS cells and then matured those cells into neurons in a lab dish. And as with his previous work, those neurons had some very peculiar characteristics. These cells transmitted signals differently than neurons made from people without PMDS. The cells also made significantly less of a protein that's involved in transmitting signals.
What's exciting is that the group exposed the cells to some chemicals that are known to increase levels of the depleted protein. Lo and behold, the neurons began firing more normally.
Now, that's not to say that the group has found a therapy. The chemicals they used have widespread effects all over the body and probably aren't suited to becoming a drug. But, it does mean that it might be possible to screen thousands of chemicals and find one that both makes the cells fire normally and can be tested in people.
One thing I find interesting is that when the group had tried a similar experiment using mice with a form of PMDS they got very different results. It will come as no shock to most of us that mice and humans are different, which is why the advent of iPS cells was such a Nobel Prize-worthy discovery. Now, scientists like Dolmetsch can test drugs on actual human cells that truly mimic a human disease. Any drugs they discover have a much higher likelihood of helping human patients rather than just curing mice.
There's more information about CIRM's autism awards on our autism fact sheet.