OTTAWA — Experts estimate that at least 600 individual genes play a role in autism, suggesting there are many different types of the developmental disorder. A fraction of the cases are caused by single-gene mutations, but some researchers suspect a vast majority are caused by multiple genetic glitches, or a combination of genes and environmental factors.
And with new technologies that allow scientists to analyze many genes, or even a person’s entire genetic code, a growing number of tests are being developed to look for mutations in some of those genes. Researchers say the new-generation tests will allow them to diagnose autism sooner and develop new drugs more quickly.
The goal is to offer children on the spectrum treatments and behavioural therapies before the full syndrome emerges and, perhaps, blunt or even reverse the course of autism’s pervasive developmental delays.
As part of its research program, Toronto’s Hospital for Sick Children is starting to use a test called high-throughput genome sequencing, which analyzes all of a person’s DNA at once for autism risk genes.
Sick Kids and Mississauga’s Credit Valley Hospital are also offering a new blood test that looks at chromosomes for missing or extra genes called copy number variations, which are another risk factor for autism.
Clinicians at the hospitals have used the test to diagnose autism since 2011, when Ontario’s health insurance plan started covering it.
Although genetic tests help only a fraction of people with autism, they provide valuable information to families.
For example, information on an inherited mutation could influence a couple’s family-planning decisions. And because some autism-related genetic disorders also carry a high risk of epilepsy, speech delays, heart defects or obesity, the results of genetic tests could help families and physicians manage potential health issues, says geneticist Stephen Scherer, who runs the Centre for Applied Genomics at Sick Kids.
Scherer says test results could also be used to identify children, such as those who already have a family member on the spectrum, who are at the highest risk for autism. The high-risk children could then be moved to the top of a waiting list for diagnosis and treatment. “In Toronto and in other places, the wait list to get a proper diagnosis or full diagnosis can take a long time, so perhaps we could use this type of test to prioritize.”
Identifying genetic causes could also help people find treatments tailored to their genetic profile. Indeed, because scientists are uncovering hundreds of genetic glitches unique to each person that increase his or her autism risk, the field cries out for individualized rather than one-size-fits-all treatments, researchers say.
To that end, researchers in Ontario are using genetic tests to identify different subsets of autism and match patients to experimental drugs that would work best for them. “We’re trying to use the genetic stratification to identify individuals that may respond to individuals drugs that we’re testing,” says Scherer.
The approach is a gradual move away from the trial-and-error approach of giving every patient the same drugs in the hope of benefiting the fortunate few.
Other scientists are focusing their research on the function of brain cells. They point out that while the genetic mutations identified to date increase autism risk, none of them guarantees that a person will actually develop the condition.
“There are reasons to think that these rare mutations cause disease, but the evidence is often not super-duper strong,” says Ricardo Dolmetsch, a neurobiologist at Stanford University. “Just because you have these genes doesn’t mean you’ll get the disease.”
A biophysicist by training, Dolmetsch switched the focus of his research to autism after his son, now 10, was diagnosed with the disorder. Changing fields was one way for him to deal with the different phases of grief that families living with autism inevitably face, says Dolmetsch. After overcoming initial denial of his son’s condition, he resolved to make finding autism treatments his personal crusade.
“Everybody puts all their hopes and dreams in their children, right? When you have a child with autism, you abandon this thought that your child is going to be a Rhodes Scholar,” says Dolmetsch. “And that takes a while. And then you realize that you have to accept him for who he is. And maybe we can do something that will help everybody.”
Dolmetsch is convinced that a missing piece of the autism puzzle lies in aspects of early brain development that are not well understood. Yet studying a human model of a developing brain is virtually impossible given that doctors can’t perform a routine biopsy, as they might on a breast or colon tumour.
Currently, researchers use lab animals to test their theories about the biology of autism. However, animal models are not ideal for understanding how the human brain works. The same genetic mutations that cause autistic symptoms in mice, for example, don’t always produce the same behaviours in humans.
To help scientists study the autistic brain, Dolmetsch has found a way to grow miniature brains in a petri dish.
Starting with a few human skin or blood cells, Dolmetsch can reprogram these specialized cells to behave like all-purpose stem cells — a method pioneered by Japanese scientist Shinya Yamanaka, whose work in this area won him the 2012 Nobel Prize for Medicine.
However, Dolmetsch pushes Yamanaka’s method one step farther. Using a precisely mixed concoction of genes and proteins, he coaxes the stem cells to turn into different types of neurons. Over months, the neurons grow into tubes before changing again to become little pieces of developing brain.
Using a slightly different chemical concoction, Dolmetsch has also created small bits of heart muscle. These tiny hearts have allowed Dolmetsch and his team to identify drugs to treat arrhythmia in people with Timothy syndrome, a rare genetic disorder that causes irregular heartbeats, anxiety and autism. The team’s 2011 study demonstrated that reprogramming the cells of people with autism could yield a relatively efficient way to screen for targeted drugs.
Indeed, as cell-culture techniques improve, the approach could be adapted to study other brain disorders, such as epilepsy and schizophrenia.
For now, Dolmetsch’s lab has produced about 150 cell lines from 50 patients, representing a range of disorders. With backing from Seattle’s Allen Institute for Brain Science, established by Microsoft co-founder Paul Allen, Dolmetsch is trying to set up an industrial-scale assembly line that could create thousands of samples of brain disorders in a dish.
The institute’s aim is to make these tissue samples freely available to researchers around the world, enabling them to speed up the process of drug discovery.
Researchers say they could use these living models of the human brain to determine where and when a gene of interest is normally expressed during development, then look for abnormalities that cause disease.
“It gives you ideas of ways to correct that specific defect and make the entire system work better,” says James Ellis, a stem-cell biologist at the University of Toronto and Sick Kids.
With their 2009 study, Ellis and his team were the first in the world to show that reprogramming stem cells to neurons was possible in people with autism. His team is using cells derived from Rett Syndrome, a form of autism that occurs almost exclusively in girls, to do high-throughput screening for potentially useful autism drugs.