Interview by Marion Gruner
What is autism and how does it manifest?
Autism is actually a family of disorders we collectively call autism spectrum disorders of varying severity. But the common themes are a disorder of language. That is a disorder of developing the normal components of language. Also social isolation. Patients seem to be cut off from normal social interactions between families and society, tend to spend more time alone fixating on objects. And another are repetitive behaviours and interests at the exclusion of social interaction. Children will prefer to spend more time, say, you know, looking at objects or repetitively doing a movement over and over again, touching an object, switching a light, rocking back and forth. And then there are these peculiar repetitive movements that involve abnormal walking or gate, limb flapping, walking on toes. Some never speak. And this tends to be the general constellation of behaviours of varying severity. And also a subgroup having gastrointestinal problems, in recent research finding immune changes and interesting bacteria in some of these patients. The group that really interested us were these groups that seemed to develop their milestones at around 18 months of age. Sadly families say these children would regress, lose their language, lose their interactions with one another and start exhibiting these behaviours, often coincident with, of all things, gastrointestinal symptoms.
Why did you start looking at autism?
Before I went into my university training and my medical training, I did a lot of work with special needs kids, and we saw these children starting to show up with these very strange symptoms, also interdispersed with what appeared to be normal intelligence. They seemed to understand what was going on but they didn’t speak. And then they were also interdispersed with these bizarre interests and bizarre cravings for food at the exclusion of all else. And then in my training in medicine I saw a lot of overlaps, where my interests were in developmental disabilities and epilepsy. A lot of the very severe cases that we would see for epilepsy and intractable seizures often had a lot of these behaviours. This time was also around the clostridium difficile outbreaks, secondary to antibiotic administration. Indeed, I noticed that some of these patients were acting somewhat strangely, what we call in medicine “delirium”. And then I was really alarmed, you know, through my training when I saw what I thought was a rare thing. Autism was originally one in 10,000 when it was first reported in the 50s, then going like to 1 in 160, 1 in 140, now maybe 1 in 90, in some studies showing as much as 1 in 40, a recent study in Korea. So, you know, you see something happening out there that was originally rare, and now, you know, you can barely talk to people who don’t know someone who has this disorder or have it in their family.
How did you get involved with Somali mothers of autistic children?
I was certainly aware of the Somali situation, the over-representation of autism from the Literature. But when I was in one of my speaking engagements, a large group came to talk to me after and told me in more detail about this situation and I became quite touched in terms of their ability to want to help to find an answer to this problem, not only for their own community but to find out for the benefit for other families in Canada and indeed the world. They probably, with their background and history, may play a very crucial role in us understanding environment and microbiological changes in the cause of autism, and probably a number of other disorders as well. Every Somali population whether they emigrated to the United States or Canada or Scandinavia have all found these diseases increasing, provided the children were born in those regions. So, in a nutshell what I think is they’ve either got our bug or they’ve got our diet that is influencing the bacteria, or a bit of both. Because doctors that I’ve talked to are quite aware of a number of other disorders that are endemic in those regions. And the same way if we travel to other parts of the world we have certain gut infections. The converse is true when they come here.
How would you hypothesize that a bug is causing a certain autistic behaviour?
Well, the peculiar thing with a lot of patients with autism is they have a lot of these severe anti-social repetitive behaviours, ticks or movements. But also a lot of them have a lot of other aspects that are intact. Sometimes very remarkable memory or insistence of sameness, so they have to remember what they consider to be good, quote unquote, for them. But part of doing things over and over again is also learning. So, I wondered if autism could be too much of a good thing? And you have this peculiar craving for certain kinds of foods, like just eating sugar or bread or pizza dough or cheese, this very rigid preference. And then, coupled with these behaviours and these memories, and this idea of there more being right in the brain of a lot of patients with autism than wrong, I wondered if there could be some interaction between the bacteria producing compounds that interact with their host to get behaviours or types of behaviours that may be beneficial for the bacteria’s survival. You know, for an example some of the behaviours that seem very strange in autism…a lot of these families have said there are behaviours like fecal smearing, spreading bacteria around. To put it in another way, a lot of psychiatric diseases could be too much of a good thing. Take for example…anxiety is a disease. But an organism that has no anxiety feels total impunity and they would not be good at surviving. So, I wondered if these compounds could be affecting food cravings, repetitive interest in things that are related to food, bizarre behaviour like fecal smearing, and it that could be the bacteria are influencing that. This is not new in neuro biology. We see a lot of examples, for example rabies. The only way you get rabies, it’s in the saliva of an animal that becomes aggressive and bites you. So, another way to look at this is that the infectious agents have evolved to control the behaviour of the host to bite and spread the disease.
So there are bugs in our guts that make us do strange things?
On closer inquiry looking at the microbiome, and some of the findings, disparate findings that have been found in autism, particularly the work with Sydney Finegold finding unique bacteria in autism, there seem to be bacteria that can produce things that go through the blood stream back to the brain, that our research has shown can make some animals do some very, very bizarre things.
So how does proprionic acid, or PPA, come into the picture?
Well, when we eat we feed these bacteria. And a certain sub-population of bacteria in the gut, including the ones that have been found in patients with regressive autism, produces a fermentation or waste product, a seemingly simple series of molecules called short chain fatty acids. This is akin to when you put sugar on yeast you get alcohol. When you put carbs or sugars on these particular bacteria they produce a compound that, in some ways is like alcohol, because it’s a small molecule, it can easily go through the blood stream and get to the brain. But it’s also slightly different. And this compound called proprionic acid, for such a simple molecule, when we looked more and more into the literature, we were amazed at the kind of things that it did in terms of cell development and metabolism, cell-cell interaction, brain development, and to brain fat metabolism. PPA is one of a panel of short chain fatty acids that are produced by gut bacteria when they ferment carbohydrates from our diet. They make proprionic acid, PPA, they also make butyric acid and they also make acetic acid. But we’re interested in PPA because it seemed to have most of the effects that seem to relate to autism.
So PPA is a problem compound?
PPA is part of normal metabolism, it isn’t good or bad, it’s part of the intermediates of fat metabolism. But also interestingly it’s in a lot of the foods that contain refined wheat and dairy and cheese, either naturally occurring or added as an anti-mould compound in foods. So we’re all exposed to it. So it seemed to be a possible link, because people were finding these over-populations of bacteria, clostridia, and desulfovibrio in the stools of these patients with autism, and you might say, well, how could a bug in a gut affect the central nervous system? So we thought, hey, here are these bacteria that every time someone eats carbs, produces proprionic acid in amounts that would fluctuate in relation to diet, and these fluctuating levels of compounds going to the brain could explain a lot of these bizarre behaviours associated with craving carbs, eating carbs, having digestive system problems, and then having these severe exacerbations of behaviour. And secondarily, when patients were given these strong antibiotics to eradicate that bug, or cut down carbs that feed the bug, some of the patients’ behaviours improved.
You had a hunch, so how did you test the effects of PPA?
The million-mile journey begins with one step. And the most rational way to look at this is say, well, if this compound has anything whatsoever to do with autism, you should be able to put relatively small amounts into the central nervous system and test it on a criteria of autism. You should see behaviours that wax and wane and look like the hyperactive antisocial repetitive behaviours of autism and tics, and the association with seizure, and you use proprionic acid and other related compounds. And then after that you delve into the biochemistry. Are we seeing the brain changes? The brain inflammation, the brain fat changes, the alterations in immune function, that are consistent with the findings in patients.
So you decided on an animal model trial. What happened in your tests with rats?
Immediately when we put a small puff of this compound, we weren’t continuously infusing it, just a little puff, within two minutes these animals started running around, running in circles, of all things walking in reverse, pushing away behaviour, and then these…a rat is not a human, but their equivalences of tall walking and limb flapping in these animals, and tics, then certain kinds of seizures that were similar to the patients. Then, when we put them in pairs we found they ran around but totally ignored each other, again showing a social impairment. And then later on, more sophisticated work done with my colleagues Peter Ossenkopp and Peter Cain, you give them choices with learning. They’ll learn a maze but they won’t unlearn, akin to us refusing to drive on the right side of the road when going from England to Canada. And also, very, very strange behaviour like spending more time with objects than normal animals, and actually having a favourite object. So, preferring to spend time with objects versus other animals. We’re in our infancy with this line of research, but it’s fulfilled every criteria so far.
Have you also tested various compounds and doses?
In order to do this research well a good scientist tries to disprove their theory. So, we started using proprionic acid and we used different doses and we got worse responses. But an important study was to take the compound that was almost identical to proprionic acid in every way except for a couple of items, propanol, which is an alcohol. This compound did nothing in terms of behaviour. So, using different fatty acids or similar compounds did not produce this effect which is an important control in doing this kind of research. Another important aspect of this research is the behavioural effects that were occurring with these compounds were very specific and very reversible. Because it’s a fat in a normal animal it was metabolised. So, you put a little amount of proprionic acid, get all these behaviours, and as the animal metabolised it, presumably within 20 to 30 minutes they went back to normal. It’s important they didn’t produce massive brain cell loss, it was a very specific behaviour, it was a very specific lipid and biochemical in-brain changes that were consistent with findings in autistic patients. So, you know, this would be the argument saying any compound could cause a behavioural abberation, that is true. But not something so specific. So, a good scientist looking at the effects of a compound is going to use varying routes, varying doses. And use compounds that are sort of like it as a control. So, for example, as you increase the dose of this compound, the behaviours become worse, the brain inflammation becomes worse so the seizures become worse. So, you get a worsening of behaviours that occur with different doses, that’s basic science. And then using the same concentration of control compounds that have very similar effects, not identical, you don’t see these effects. And then we’re certainly not fixating on proprionic acid, we’re looking at all the fatty acids that are produced by gut bacteria.
So far you’ve only talked about adult animals.
After doing the groundwork with the adult animals and understanding the biochemistry, the logical response is to go back, because it is a developmental disorder, to go to infant animals, rat pups, to expose not just their brains but through diet, through peripheral exposure. And we found that these animals, even with these brief exposures to these gut fatty acids kind of mimicking an early gastrointestinal dysbiosis, even these brief exposures when the animals grow up they show behavioural effects. And in addition, we are looking at pregnancy with animals, when the pregnant, mother rat is exposed to proprionic acid and looking at the long term effects of that. So, the model enables us to rationally and ethically kind of go from conception to adulthood looking at the exposure or reexposure of these compounds. And they are not mutually exclusive. You could see a person or an infant being exposed to this compound in the womb, but maybe reexposed later as they got introduced to other bacteria or an altered diet. But it’s a way that we can test this ethically to increase the rigour of being able to later look ethically at human patients.
How do bacteria interact in the human gut?
If you’re a person coming into, like in a ship going into your microscopic milieu inside of your digestive tract, it would be like looking at a rainforest. You would be seeing certain kinds of bacteria huddled in this little corner interacting with others, you’d have these things equivalent to big rainforest trees and branches interacting. You’d have other animals just like other bacteria, like animals, like insects and birds living inside of the tree. You would see this complex interaction between predator and prey. You’d also see these interactions that we all see in biology, different organisms in a rainforest interacting to their mutual benefit.
What causes changes in the makeup of bacteria?
Just as people come into a rainforest and clear cut it and cause massive damage to this eco system, some irreparable or have other species growing in, so can antibiotics, both in the patient and in…a patient in a hospital or in general society cause major alterations in these bacteria. So these alterations that can change these interactions regarding immune function and normal brain development and whole body development could have major altercations if things like antibiotics or other factors change the bacteria in the first few months of life.
Talk about those first months, years.
It’s an under-appreciated fact that, you know, when we come into this world, at least as far as we know in research, we have no bacteria in our digestive tracts. So here we are being pushed out through the birth canal into this world full of bacteria. So the first bacteria coming from mom, good or bad. Then bacteria come in, if you’re in the hospital you’re dealing with other people, you’re getting bacteria from the mother whether you breast feed or not. Again, a lot of things can alter this, whether you have a C-section, whether or not, for another reason you were sick and you spent the first few weeks in a hospital rather than being, you know, like we want to, get you out within a couple of days. All these things can start coming into play with this very complex interaction to try to, that would normally produce a stable rainforest in your gut, and it may lead to triggers of a number of diseases.
How do the bacteria influence us?
These little creatures that live in our gut may change who and what we are, all the way from disease processes, and even with our work, behaviour and even personality. So, for example, whether there’s more or less of a certain bacteria, each of these bacteria, when we eat we feed them. So they need fuel, and like us they produce waste products. So, a lot of these waste products can be beneficial to us, that’s the work we’ve been looking at with these compounds called short chain fatty acids. But they also produce a lot of other factors that deal with immune function, inflammation, which have both positive and negative effects. And they talk with each other. And one bacteria’s waste product is another bacteria’s food. It’s an order of complexity. Orders of magnitude more than I would have ever conceived back in my training.
Who’s in charge, us, or our gut microbes ?
Microbes are the oldest living creatures, and people have made the argument that their biochemistry and biology has evolved to make us kind of like a spaceship, a shell to protect them from the outside world and have us do their bidding. It seems out of like a bad movie, but biologically we shouldn’t be so ego-centred to think that we’re the centre of biology. We do know, even in our basic medicine, that here gut bugs are producing compounds to protect us from cancer and keep our blood being able to clot. If you look at this at a larger level, it’s in their best interests…although this is through evolution, they’re not consciously thinking, to keep us around. So, we wonder if it’s occurring and they’re making certain compounds that are beneficial? We’re kind of part and parcel, their metabolism is part of our metabolism. I wonder if it could be taken farther into the point of behaviour. Could the bacteria play a role in altering simple behaviours? For example could a bacteria produce behaviours like turning or fixating on an object that would presumably relate to the organism being able to eat or look at an object? Could that be beneficial until it becomes too much? Put in another way…as you become more specialized it can become more pathological. So, this could be a beneficial effect of the microbiome kind of acting as an overseer to affect some aspects of human behaviour. Normally beneficial, but in the case of autism, when you have an over production of something that’s good, getting a disease process, too much learning and memory becomes obsession. Too much vigilance become anxiety. Too much of an interest in something becomes so restrictive that it’s useless. So, this may be another way of looking at some of the behaviours and explain why a lot of these kids with autism seem to have aspects of behaviour that’s intact and when some of them appear to have improved, they seem to be hyper competent in some things. So, it’s an intriguing hypothesis and although it’s completely in its infancy, things that we found seem to support it.
Why do you think autism is found in geographic “clusters”?
When you look at the increase in autism over time, you don’t kind of see something that’s gradually increasing, it’s kind of going up, I’m being very general, but semi-exponentially. So these things with an increase seem to follow an infectious picture, and again, these higher areas of clustering tend to be areas that are urban. I was intrigued by one map showing the spread of clostridia being related to antibiotics. And showing tons in the northeast, tons in Texas, tons in these urban centres where there’s a lot of high density, people coming and going. And it’s very interesting in that that map seems to overlap autism, so it does fit in. These gut bacteria, they don’t have wings, they don’t fly from place to place…they basically occur by just touching things or in food or in diet. It’s impossible not to be exposed to these things. I don’t want to be alarmist, but these are possible ways where people are in close proximity, in close, fecal oral contamination are at a higher probability of spread. So, that was one way to look at the possible increase as opposed to just saying that there are certain other environmental factors, that aren’t appreciably increasing, like valid work, important work, looking at metals or certain pesticides and such, they’re not increasing drastically day to day, but these disorders are increasing. Remember they are interacting, though. A lot of these factors do affect bacterial populations as well. So, it seemed to fit with my rudimentary epidemiological experience, an infectious picture.
Why did you decide on a team approach in setting up the Kilee Patchell-Evans Autism Research Group?
There clearly are all these different camps of people having their various theories for autism. Good people, good researchers, but sort of concentrating on one aspect. For example, there’s people doing good work, looking at genetics. There are people saying, hey, let’s look at immune function, let’s look at mitochondria, let’s look at gut or diet or bugs or epilepsy, metabolism. So, what I wanted to do was try to bring, from all the disparate theories of autism, try to say is there something common to all these effects, but bring together a group of people, initially here at Western, but it kind of expanded everywhere, who are experts in these different aspects of neuro science. Our hope is in trying to establish networks between these groups that we will be able to test hypotheses and exchange with people that have far more expertise in any of these fields. We want to look at how environmental factors affect genetics. We want to be able to look at all these metabolic biomarkers of metabolism and fats and how we can test them in various treatments in these animals. And we also want to be going out with the epidemiology experts to be able to do good studies looking at multiple environmental factors, both in the general population and in these unique populations like this Somali group. We have never said proprionic acid is “the way”. It’s a way to look at something. It’s a way to exchange information openly between groups. Because regardless of people’s view in this disorder and approach, they all care about trying to help these families. I liken our work to, sort of, when people were looking at diabetes, it seemed like a hopeless disorder and the children were sick and had multiple problems and got better or worse when people changed their diet. Sounds very familiar, doesn’t it? But when people started to understand metabolism and how things connect to each other in a chain, miracles happen. That’s my hope.