Scientists may have made a major breakthrough in understanding the biology of autism. But a crucial part of the scientific process is replication–having other scientists repeat the experiments and confirm the results. In this case that may not happen for a very long time.

It isn't that scientists don't want to or don't know how to. It's because they don't have enough brains.

"We have so little to study, it's just egregious," said Thomas Insel, director of the National Institute of Mental Health. People don't line up to donate brain tissue like they do for other organs or blood, Insel wrote on his blog a few months ago. One reason might be squeamishness, he suggested: "Perhaps because identity, our sense of self, resides in our brains, not our kidneys."

>'We have so little to study, it's just egregious.'

Another factor may be that signing up to donate your brain takes a bit more initiative than just merely checking the organ donor box when getting your driver's license. Whatever the reasons, the recent autism finding illustrates why it matters.

Last week, scientists reported they'd found something very strange in the postmortem brain tissue of autistic children: tiny patches of the cerebral cortex where the neurons weren't neatly arranged in layers as they normally are. The study used brain tissue from deceased autistic children (drowning was the most common cause of death–autism itself doesn't shorten the life span).

The scientists who led the study believe it may be an important discovery. Other researchers worry the patches could be an artifact. Everyone agrees that replicating the study is crucial, but the sad truth is that's going to be really, really hard to do.

In fact, the researchers used all of the tissue that met their criteria in two of the biggest brain banks with tissue from autistic children (the tissue had to be extremely well-preserved to work with the molecular labeling methods they used). The grand total? Twenty-two samples: 11 from autistic kids, 11 from non-autistic kids of a similar age.

"This was pretty much the 'universe' of possible high quality brain tissue from critical regions in very young autistic and control cases," said Eric Courchesne, a neuroscientist at the University of California, San Diego and a leader of the study. "We still have blocks here in preparation for the next experiments, but elsewhere there may not be much left."

Scientists studying autism and other brain disorders have only a few good tools at their disposal. Any scientific technique has pros and cons, but sometimes there's no substitute for studying human brain tissue.

Brain imaging methods like MRI scans can show gross abnormalities, but they're far too coarse to reveal abnormalities at the cellular and genetic level like those described in the new paper. If a person has massive brain loss from something like Alzheimer's disease, an MRI scan can pick that up. Otherwise, it's a lot trickier. Brain scan studies on autism, for example, have been hard to sort out.

Unlike MRI scans, lab animals can be incredibly useful for genetic and cell-level studies, but it's not always clear how well they match human diseases, especially for neuropsychiatric conditions. It's been exceedingly difficult, for example, to genetically engineer mice that reasonably mimic the symptoms of autism.

Many scientists are excited about a newer approach to studying brain disorders that involves taking skin cells from a patient and converting them into stem cells that can be turned into neurons. That's exciting because it gives scientists a chance to experiment with neurons from real human patients. But even that strategy has limitations. For example, getting those lab-raised neurons to organize themselves into the complex cellular architecture found in a whole brain is well beyond what's currently possible. For some studies, that may not matter. For others, it almost certainly does.

None of those methods–brain scans, animal experiments, or reprogrammed stem cells–could have revealed the type of abnormalities reported in the recent autism study. But now it's going to be difficult to verify that the findings are real.

"The problem is, they have looked at just about all of the biologically suitable tissue that's available for study," said Robert Hevner, a neuroscientist and neuropathologist at the University of Washington. Hevner is skeptical about the findings, but says he's keeping an open mind and would like to see it followed up. He's not optimistic though. "It's going to be a very hard study to try and replicate," he said.

A new study found patches of disrupted cortex (dark area, top center) in the brains of people with autism. Image: Stoner et al. NEJM

One of the two autism brain banks used in the study is run by the National Institute of Child Health and Human Development. It contains 43 brains from people with autism and no other complicating conditions. The other, the Autism Tissue Program, has 170 brains. Those numbers may not sound so bad, but keep in mind that researchers usually can't use just any piece of brain tissue–they want to examine the bits they think are most affected by the disorder they're studying. If they need tissue that has been preserved well enough for molecular studies, their options are even more limited.

Even worse, autism researchers suffered a major blow in 2012, when a freezer malfunction at Harvard in 2012 compromised 147 brains, about a third of them from people with autism.

A quick and dirty calculation using the CDC's newly-released autism estimates (now up to a startlingly high 1 in 68 children) with the 2010 Census count of kids under 18 (72 million), suggests close to a million children could be living with the disorder. Of course most of them are ineligible for this kind of study because they're living, and some families will never go in for brain donation. But still–the discrepancy between the number of people with the disorder and the number of brains available for study is enormous.

The severity of the shortage varies across conditions and across age groups, says Michelle Freund, a program officer at NIMH. "There's probably not a shortage of tissue from people with Alzheimer's disease," Freund said. "There's certainly a shortage of healthy controls across the lifespan," she said. The shortage is especially acute for tissue from children and people with less common disorders.

NIMH recently launched NeuroBioBank, a project that aims to get more tissue in the hands of more researchers. It provides funding to five brain banks to create a standardized register of tissue samples and establishes rules for sharing them. The agency expects to add one or two more brain banks to the network this year and hopes to continue to expand it, Freund says.

So how do you go about donating your own brain?

Checking the organ donor box on your driver's license isn't enough. You have to sign up with a specific brain bank. NIMH maintains a website for potential donors interested in registering with one of the five brain banks participating in their NeuroBioBank program. Patient advocacy groups often maintain lists of brain and tissue banks (and in some cases even run them themselves, as with the Autism Tissue Program, which is expected to relaunch soon as the Autism Brain Net). Googling "brain donation program" plus the particular disorder and/or institution you're interested in should get you started.

It's up to you, of course. By all means make the most of your brain while you've got it. But when the end inevitably comes, why let such a precious resource go to waste?