When his son Alexei was first diagnosed with autism at the age of two, Christopher LePoer took some time off work to try to understand why his child couldn’t speak, had highly irregular sleep patterns and walked solely on his toes. After weeks spent ploughing through medical websites and research he came to one unsettling conclusion: scientists didn’t understand either.
He also read that researchers needed brain samples to study the condition, and remembers marvelling at how difficult it must be to collect them. After all, autism, though potentially disabling, isn’t fatal. “I thought, wow, it’s got to be almost impossible for them to get the research materials to find out what they really need,” LePoer says.
Unfortunately, on 13 May this year he suddenly found himself in a position to help them out. At age four, Alexei, the fifth of the LePoer’s seven children, opened a window-screen latch, slipped out of a first-floor window and slid down to the ground. A few minutes later, his body was found in a nearby swimming pool.
A request for Alexei to become an organ donor reminded LePoer of his investigations two years earlier, and he and his wife quickly decided that something good should come out of Alexei’s tragic death. Less than 24 hours later, packed in an ice chest carried by a courier, Alexei’s brain was delivered to the Harvard Brain Tissue Resource Center in a nearby Boston suburb.
Harvard University’s brain bank, which is supported by the advocacy group Autism Speaks, is one of only a small handful in the world that collects the brains of people who die with autism. When Alexei’s brain arrived in mid-May, the collection had about 150 samples – the most anywhere. A few weeks later, though, a freezer containing 54 of the autism samples broke and its two alarm systems failed to sound for reasons that are still unknown. By the time the failure was discovered days later, the brains had thawed and were largely ruined.
Fortunately, Alexei’s brain survived, but the malfunction is a tragedy for others: a devastating loss to many families that had donated a deceased loved-one’s brain, and a critical loss to autism researchers. At the current rate of brain collections, it will take a decade or more to recover the amount of research material and time lost, says Carlos Pardo, a neuropathologist and associate professor of neurology at Johns Hopkins University, who has used the collection for his studies into the role of the immune system in autism.
It is resources that scientists and the community could ill afford to lose, leaving the question of what to do next. After all, how can autism researchers possibly recover from losing an invaluable source of material that was already in short supply?
For every parent who makes the heartbreaking decision to donate their child’s brain to autism research, there are hundreds if not thousands of scientists who are extremely grateful that they have. Studies on donated brains are considered to be the gold standard for understanding the origin and natural course of the condition, as scans don’t have enough resolution to detect any biochemical changes inside living human brains. Animal models can’t help, either. “Mice don’t get autism,” explains Roger Little, a senior advisor at the US National Institute of Mental Health. “The only way we’re truly going to understand diseases [like autism] is to have the tissues in which the diseases occur, as well as healthy control tissues to compare them to.”
Researchers say that differences in donated brains could help figure out how to help autistic children learn to speak, interact more easily with others and avoid the repetitive behaviours that define the condition. Whereas brain banks for schizophrenia, Parkinson’s and bipolar disorder have been around for decades, interest in collecting and looking at autistic brains began only about a decade ago, said Margaret Esiri, emeritus professor of neuropathology at Oxford University and director of the UK Brain Bank for Autism and Related Developmental Research.
The search began so late in part because the awareness of autism has only risen in recent years, now turning up in one in every 88 US children, according to the latest figures from the US Centers for Disease Control and Prevention. It also took a while to focus on the biological aspects of autism. As recently as the 1960s many scientists blamed the condition on bad parenting; decades later some still saw it as primarily a behaviour problem.
But science is now ready to fully explore the biology of the autistic brain, says Esiri. “Until the last 20 years or so, we probably didn’t know enough to be able to make the most of brain tissue,” she says. “It seems an ideal opportunity to strike now.”
However, the loss at Harvard means there are fewer than 200 autism brains stored in banks in the US and Europe. The University of Maryland has a collection of about 50; Oxford University’s Brain Bank for Autism and Related Developmental Research has collected 21 in its three years of existence; and a year-old bank at the University of California, Davis’ MIND Institute has four. The banks, with the support of the US federal government, are collaborating now, sharing what they learn from each brain through an online database.
This historic lack of brains available for autism research “is just pathetic,” says Cynthia Schumann, head of the MIND Institute’s Brain Endowment for Autism Research Sciences (BEARS) program.
Two hundred brains might be enough if autism were a minor condition, caused by a single factor and having the same set of symptoms in everyone. But it’s not. Some people are significantly disabled socially and intellectually; others see their autism as giving them a unique and valuable perspective on the world. Some cases are caused by single-gene mutations, others are of unclear origin, triggered perhaps by dozens of genetic flukes, or something in the environment, or both. Around 20% of children with the diagnosis seem to grow out of many of its symptoms, the rest feel its effects for life.
To really figure out autism, scientists say they need to examine brains that represent this full spectrum of conditions, both at the earliest stages of life when the brain is first developing, and later, when patterns have been set. And this means they need something along the order of several hundred donations.
One person who takes brain bank donations personally is Manuel Casanova, a neuropathologist at the University of Louisville, in Kentucky. He started two brain banks earlier in his career and shifted much of his research focus to autism after his grandson was diagnosed on the severe end of the spectrum. The boy, the son of his eldest daughter, was named Bertrand after the British polymath Bertrand Russell, because everyone expected that any child of his daughter’s and her husband’s would be extremely intelligent. But Bertrand, 5, can’t speak, scores very low on IQ tests and lacks basic motor skills.
Brain tissue research hasn’t been emphasised enough in autism research, he says. Genetics research may take decades between a basic discovery and a treatment, but Casanova thinks the route could be shorter for brain research because it focuses on the actual functioning of the brain. “We should fund studies that are able to make a difference now for the lives of the patients,” he says. “Finding something abnormal within the brain from postmortem studies can make a difference.”
Casanova himself has used the tissue from the Harvard brain bank to test his hypothesis that autism is basically a wiring problem. The brains of people with autism, he thinks, are very good at forming short-range connections, but not as good at forming long circuits that integrate different parts of the brain. This may explain why people with autism have narrow areas of tremendous strength – say an ability to remember detailed train schedules, work complex mathematics calculations in their head, or create impressive works of art – but also global weaknesses, like language and social skills.
His work has led to clinical trials for a possible treatment for autism, using transcranial magnetic stimulation to change the levels of excitation in the brain. The hope is that the change will allow the brain to rewire itself, thus improving some of the negative symptoms.
When a donation arrives at a brain bank, investigators carefully slice it into sections. Roughly half the brain is preserved in formalin – an updated version of the smelly chemical used on dissection animals in science classes. The other half is thinly sliced and stored in a deep freezer at -80C to keep the chemical state of the brain cells intact.
Preserving and protecting each brain costs about £800 ($1,260), says Esiri.
Sometimes, the brain is scanned before being carved up. A technology called Diffusion Tensor Imaging can show the connections between one part of the brain and another. Some researchers also want other tissue – from the gut, blood, skin and teeth – which several of the banks have begun collecting as well.
As scientists request tissue, small samples are carved out of the brain and sent off. Most researchers can do their work with no more than 2 grams (0.07 ounces) of brain tissue – or just 100 mg to examine only the DNA – out of a total of about 1,200-1,300 grams in the average brain.
“The problem is it’s very difficult to isolate 100 mg of frozen tissue and keep it frozen,” says Ronald Zielke, director of The Eunice Kennedy Shriver National Institute of Child and Human Development Brain and Tissue Bank for Developmental Disorders at the University of Maryland. “In theory there’s a lot of tissue there, but that’s not necessarily the reality,” because researchers may want to focus on a specific and tiny area of the brain.
Zielke said his brain bank, which includes a wide range of developmental disorders, ships out about four samples a day, all year round. “We have over 860 researchers in 23 countries that have received tissue from us since 1991,” he says.
Each brain can be used by as many as 50 or 100 different researchers, he said, but it is not inexhaustible. New brains are needed all the time to keep up the supply, he said.
To be most useful to science, a brain has to be frozen within 24 hours of death. After that, the proteins in the brain start to degrade, though the structure – the relative size of different parts of the brain, for instance – may still prove useful.
This means reaching out to families at the worst possible time, when their loved ones have just died, a responsibility that often falls down to local medical examiners in US. “Medical examiners are absolutely critical for autism research,” says Zielke. “Without their support and participation, [efforts to get brain donations] will limp along.” His brain bank has received a grant from the Autism Research Institute, an advocacy group, to educate medical examiners about the need for brain donations and the proper procedures for ensuring that brains can be used for research. “The probability of any one individual dying is relatively low, thank goodness,” says Zielke, but every year, one or two people with autism die in just about every state. “If all medical examiners participated, there would be no shortage of autism tissue for research. In one or two years, we’d have enough,” he says.
Medical examiners are also important because they have access to people who don’t have autism, and so aren’t reached by advocacy groups. “We need typical brains just as much as ones with autism,” says Schumann. Without receiving these age-matched “controls”, the researchers wouldn’t know which brain features are typical and which are characteristic of autism.
Zielke says he doesn’t judge parents if they decide not to donate a brain at a time of such crisis, but Schumann said she’s been amazed at how generous family members can be despite their grief. She said she initially thought the hardest part of her job would be asking families to donate. “If anything, they tell us thank you, which is just not what I expected.”
Christopher LePoer says he’s still excited by the idea that – even in death – Alexei will be able to make a contribution.
“I only had four years and it wasn’t close to enough, but I’m so grateful that I did have four years with him. He was an amazing little boy. Amazing,” LePoer says.
He says he keeps reliving the events leading up to his son’s death, wondering what he could or should have done something to prevent it. “I don’t go 5 minutes without thinking about him,” LePoer says. “It’s just: what if, what if…”
Knowing that Alexei’s brain is now helping someone else gives LePoer what little peace he can find.