Brain Development

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by Marianne Meadahl
Photograpy by Dina Goldstein

Looking at Autism and Schizophrenia in a New Way

Bernard Crespi has been quietly at work connecting research across the diverse fields of molecular genetic psychiatry and evolutionary biology – all with the view to better understanding the roots of two key brain disorders: autism and schizophrenia. But the SFU evolutionary biologist found himself in the spotlight last fall after a new theory he devised with sociologist Christopher Badcock from the London School of Economics prompted international headlines.

At the crux of the theory is the idea that autism and schizophrenia are opposites of one another. The research piqued the interest of the New York Times and led to a story by Benedict Carey on Crespi that described the work as “a sweeping theory of brain development that would change the way mental disorders like autism and schizophrenia are understood.” According to Carey’s article, the researchers’ new idea “provides psychiatry with perhaps its grandest working theory since [Sigmund] Freud, and one that is grounded at the forefront of science.” The description was echoed in a bold headline on the front page of the Vancouver Sun (“SFU biologist’s theory called one of greatest since Freud’s”) and has since stirred debate in scientific circles.

Crespi and Badcock theorize that autism and schizophrenia develop depending in part on whether certain genes in the mother or father are imprinted during fetal development. Imprinting is caused by a biochemical change in the cells that hold the genetic material passed on in vivo. It works like this: a strong bias toward the father’s genes steers development toward autism, while a bias toward the mother’s genes pushes the growing brain toward a hypersensitivity to mood and an increased risk of schizophrenia.

Autism is characterized by impaired social interaction and communication. Schizophrenia typically has a number of symptoms on the other end of the spectrum – paranoia and mood swings. The scientists’ theory stems from the view that things other than mutations could change the behaviour of genes.

The work began as something of a research diversion for Crespi, the 2001 recipient of the E.O. Wilson Naturalist Award for his advances in evolutionary biology. Until recently, he was better known for his study of the social behaviour of insects and other animals. In fact, he knew nothing about subjects like psychiatry or psychology and is unashamedly self-taught, pinning the effort on a fascination that grew over the years with the role of genetics in brain development and disorders – and in disease in general.

The scientists’ theory stems from the view that things other than mutations could change the behaviour of genes.

Crespi met Badcock at a lecture at SFU 10 years ago, and although the two exchanged similar views on genetics and the brain, they didn’t reconnect until nearly six years later after Crespi read a paper by Badcock and sent him a note. The two began corresponding and decided to collaborate.

“The term autism was coined about a hundred years ago by Eugen Bleuler while he was working on schizophrenia, to refer to the patient’s withdrawal from reality,” Crespi notes. About 40 years later researchers began describing autism as something different from schizophrenia, but the idea was not broadly accepted as most saw autism as some sort of manifestation of schizophrenia, he adds.

“ ‘Childhood schizophrenia’ is what it tended to be called early on,” says Crespi. “Through the sixties and seventies there was a lot of confusion in terms of understanding and diagnosing the disorder. People gradually began accepting that the two were different, that autism wasn’t some subset or indirectly related. And that’s where things have sat for 20 years.”

Crespi and Badcock’s investigation of the genetic basis for each condition showed that while there were imprinting effects in both disorders, those effects had never been considered in terms of evolutionary theory. And while imprinting is only one of several contributing causes to the two disorders, it’s a factor that clearly shows their opposite nature, say the two researchers.

Crespi and Badcock collected and studied physiological and neurological data on people with both disorders, as well as data on their cognitive and behavioural characteristics. Their findings were published in Nature and other academic journals.

“In the paper we prepared for Behavioral and Brain Sciences, we went from the psychological level all the way down to the genetic level looking at psychological traits: developmental sorts of traits, brain anatomy traits, brain imaging traits. And we looked at the genetics and described evidence from all of those different levels – all supporting the idea that these should be considered opposites to one another.”

Crespi is working with new genetic data to test the theory’s ideas, and he plans to plug away on his own. He admits that there are those who don’t have a lot of use for hypotheses and that “unless they are absolutely convinced that they can benefit and get better results from these ideas, they’re not really going to pay that much attention. There is a ton of data out there. I can use it to test the ideas the best I can, and keep publishing papers. Eventually people will notice.”

Crespi admits he’s still learning. He hopes to meet key players in the psychiatric field at symposiums in the year ahead. The work will take time, but Crespi has patience. He remains grateful for the window of time he had for the laborious self-imposed study that instilled him on the research path – time that was afforded after he received a Killam fellowship in 2005. The award recognizes research of outstanding merit.

“When I got the Killam fellowship, I was originally planning to write a book about social evolution in animals. At the same time I was getting going on this, and I thought, I have to do this; it’s far more exciting.

“I had two years without teaching or administrative duties when I could devote my time to teaching myself about psychiatry and molecular psychiatry and psychology – all subjects I knew virtually nothing about.”

He pored through journal after academic journal. “It was
brutal. If you ask my kids what I do, they’ll say that Daddy sits at the computer – they think that’s what daddies do,” says Crespi, a busy father of three children all under the age of 10.

“I think it’s probably good in some respects to learn things that way – to go headstrong at a subject without being indoctrinated by teachers or advisors. I paced myself.”

Growing up in Chicago in a family where education was strongly valued – four of his seven siblings are also university professors – he remains a consummate learner. His main “deficit” after cramming for months on end remains knowledge of the neurosciences. “You’ve got the evolutionary genetics on one side, then the psychiatry, symptoms, and disorders over here,” he animates. “And neurosciences in the middle.

“It’s much more technical and specialized in some ways than other disciplines – and it should be. The human brain is probably the most complicated structure in the universe, with trillions of connections and hundreds of different types of connections, just fantastically complicated. For me, the mystery is not so much in the mechanisms as it is in the evolution of the way and how the disorders of the human brain are related, and how it has evolved – and the genetic basis of that.”

Working on the social behaviour of insects, which often led him on exotic searches for his subjects, including Australian social insects known as thrips, gave Crespi the basics on sociality.

“What I am doing essentially is taking all of that theory and background and moving it over onto humans – the brain, genomics, and genomic imprinting,” says Crespi. “It’s fascinating stuff, but it takes awhile to get an appreciation for how the field has developed. The genetic basis of these disorders is really an amazing story that someone should write a book about.”

Crespi hopes to see studies in his research lab at SFU grow to include the evolution of human health and disease, the subject of a popular course he now teaches. He argues that an evolutionary perspective should be brought into areas such as mainstream cancer research, noting that cancer cell activity in part evolves in the context of conflicts between certain maternal and paternal genes.

Crespi hopes to see studies in his research lab at SFU grow to include the evolution of human health and disease, the subject of a popular course he now teaches.

In a chapter written for the forthcoming book Depression: Transactional Approaches to Understanding and Treating (Oxford University Press), Crespi points out that the fields of molecular genetic psychiatry and human evolutionary genetics have burgeoned over the past 10 years but continue to develop in virtual isolation. “Study of the evolutionary genetics of psychotic-affective disorders is thus in its infancy,” he writes, “but it holds enormous promise for future progress in both domains.”

Crespi is hopeful advances will continue. “The field is moving at just a fantastic pace because of the way technology has developed. It’s a tremendously exciting field right now,” he says. “In fact, genetic and genomic technology is advancing so rapidly that it’s possible to get data that people wouldn’t have dreamed about five years ago. In a couple of years, we’ll easily have whole genome sequences for large numbers of people, and that will be the data we’ll be able to use to figure out the genetic basis of these disorders.”

To what extent their theory is embraced by the scientific world Crespi says remains to be seen. While some experts say it is not enough to overturn current thinking about disorders as distinct as autism and schizophrenia, the Carey article in the New York Times surmised that Crespi and Badcock have “infused the field with a shot of needed imagination and demonstrated the power of thinking outside the gene.”

Crespi’s goal is to build bridges between scientific spectrums and promote the need to open up the field of psychiatry and its related disorders to include the study of evolutionary genetics.

“The founder of modern psychiatry, Emil Kraepelin, said about a hundred years ago that there are two kinds of people who work in psychiatry: those who are interested in it and those who stumble upon it, and the latter are sometimes reasonable.
I hope I’m in that company,” says Crespi.