Cracking the autism code

Headlines, Research — By on October 11, 2017 12:11 pm

Dr Jessie Jacobsen and the Minds for Minds team at the University of Auckland have already made internationally significant discoveries in the area of genetic sequencing to isolate the causes of autism and neurodevelopmental disorders. Julianne Evans reports.

Life can be a lonely journey if you experience the world very differently to other people but don’t know why. This is often the fate of many on the autism spectrum and their families. The sharp rise in conditions included in the classification of autism spectrum disorder (ASD) has led some to controversially label it an epidemic.

But what if you could get an accurate genetic diagnosis for autism? Could it lead to earlier detection, more specific and effective management and, ideally, a brighter future, particularly for those affected by ASD and their families?

Imagining that outcome, and already making significant progress towards it, is what drives neuroscientist Dr Jessie Jacobsen, School of Biological Sciences. It was her fascination with the genetics underlying human conditions, especially those affecting the brain such as Huntington’s Disease – an area in which she’s worked with renowned brain researchers Distinguished Professor Sir Richard Faull and Professor Russell Snell – that led her to autism: a pioneering field rich with possibilities.

It’s now estimated that one in 68 people are on this spectrum in the US, and in New Zealand it mildly or profoundly affects more than one in 100 of us. These are large numbers, even allowing for wider screening and more accurate diagnosis and the re-categorising of conditions such as Asperger’s Syndrome under the umbrella.

Officially defined as having “impaired social or communication skills, repetitive behaviours or a restricted range of interests”, ASD’s causes have been a matter of heated debate and “many urban myths,” says Jessie.

Some combination of environmental and genetic factors appears to be the consensus, with the latter usually different for each individual, depending on their unique gene variants.

And rather than a single “autism gene,” scientists have identified multiple genes that in particular combinations can add up to a risk factor for ASD, while admitting that many genetic factors remain mysteries to be discovered.

Acknowledged as a high flyer by senior University colleagues such as Emeritus Professor Louise Nicolson and former Dean of Science, Emeritus Professor Dick Bellamy, 35-year-old Jessie has already had a distinguished early career.

As part of her post-doctoral research, she worked at the Center for Human Genetic Research at Massachusetts General Hospital and Harvard Medical School: “I was fortunate to be able to learn from and now collaborate with colleagues in Boston who work on particularly complex, and previously unknown types of genetic variation.”

Returning to New Zealand in 2012 on a Neurological Foundation of New Zealand repatriation fellowship, Jessie was awarded a Rutherford Discovery Fellowship to help establish a genetic research project, based at the University, for autism spectrum and other neurodevelopmental disorders.

Working collaboratively with her team, which includes Professor Russell Snell, Associate Professor Klaus Lehnert and a number of postgraduate students, Jessie’s leading-edge project invites members of families affected by autism to submit blood or saliva samples. The team then examines or “sequences” the DNA.

This “sequencing” is carried out to determine the precise order of nucleotides within a DNA molecule. Jessie explains the process.

“Chromosomes are a thread-like structure of nucleic acids found in the nucleus of most living cells, and they carry genetic information in the form of genes. The genetic code consists of four letters: A, T, G and C, and each represents a chemical building block of DNA, the molecule that encodes the information necessary to build life as we know it. Once sequenced, we compare an individual’s genome (a person’s complete set of genes) to a reference to see what is different, rare and biologically relevant to autism.”

“The changes in DNA can be complex,” says Jessie. “It’s like proofreading a book; you’re looking for things like missing paragraphs or letters, repeats, changes in the way the words read, an extra volume of a whole book, something that stops mid-sentence or a deletion of a whole sentence, even a single letter change – all of us have different variants that make us unique.

There are so many ways that our DNA is stitched together.”

The “fun time” is when the team examine what they’ve discovered and interpret what might be a causative variant for autism or a related neurodevelopmental disorder.

“We get in a room together and go through all the variants – people’s brains have different approaches to the same information, so it’s always a team effort – we continually learn from each other, and have a lot of fun in the process.”

Jessie says the genetics team is keen to move some of its research findings into clinics here: “We’ve just received funding from ‘A Better Start’ national science challenge and ‘Cure Kids’ to help us develop a clinical panel of the most frequently-affected genes in children diagnosed with autism.”

“In this way we can contribute to a future in which the clinician will have a cost-effective panel of genes that they can directly check when making a diagnosis.

“Historically, there have been many changes in the behaviourally-based diagnostic criteria, which can make consistent diagnosis a challenge. We’d like to help improve that,” she says. Jessie believes families affected by profound autism deserve all the help they can get.

“An earlier diagnosis leads to earlier and more targeted interventions, which can make a big difference.” Once they have individual DNA results, clinicians like Auckland neurologist Dr Rosamund Hill, who is an honorary academic in the School of Biological Sciences, along with clinical geneticists at the Auckland District Health Board, authenticate the results and deliver them back to the families.

There have already been some exciting breakthroughs.

“Some things we’re discovering for the first time in New Zealand, which is really exciting, or we are discovering variations that have been seen only a few times in other countries – which helps provide evidence that they are indeed causal,” says Jessie.

Researchers are able to deposit or publish their findings on an international database so that knowledge is shared. She says that particularly now, as a mother of a young child herself, she can understand how parents feel about getting a diagnosis.

“I underestimated how much families appreciate just having an answer. There can be a lot of guilt and wondering: ‘What could I have done to prevent it?’ With the right knowledge, we’ll be able say, ‘It’s nothing you’ve done, nothing that could have changed things’.”

One such family has a daughter, Sofia, who is affected by autism. Sofia’s father feels incredibly grateful for the work Jessie and Minds for Minds is doing. “The involvement in the project was an opportunity for us to understand more about our daughter’s condition, which had been described as global developmental delays, and as being on the autistic spectrum,” he says.

He says the research resulted in findings that were far more valuable than he’d hoped for: “This research picked up a rare chromosome disorder called 2q37 deletion. A diagnosis is something we’ve never had and this has made it possible for us to understand so much more about why our daughter is like she is.”

He says it’s been a big relief and helped the family understand that issues they were aware of, such as hyper-mobility, are actually features of 2q37.

“It’s enabled us to get further tests done for things specific to 2q37 such as potential heart defects and kidney conditions; thankfully the tests have all been positive so far,” he says.

There is still a long way to go in understanding the biological basis of autism, and Jessie is the first to acknowledge that a genetic approach is not always going to be the only answer, which is why the Minds for Minds research network was established.

“Children with autism seem to have an increased incidence of gut issues for example, so work is currently being done by Associate Professor Mike Taylor in Minds for Minds, investigating the microbiology of the gut and gut health. “But if you can improve diagnosis, it’s easier to go forward. Finding an answer, even for one family, is important, so we can say, ‘here’s the DNA variation, here’s what caused it.”

This question is being addressed by other minds all over the world: “Microbiologists, physiologists, psychologists, and importantly, our wonderful New Zealand clinicians. The only way we can tackle a complex issue like autism is if we all work together.”

Jesse and her team would like to thank all the families involved in this research, as well as the Oakley Mental Health Foundation, the IHC Foundation and the Minds for Minds Charitable Trust.

More information about this project can be found at www.mindsforminds.org.nz

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