Prof. Jeremy Nicholson Interview

Interview by Christopher Sumpton

Why has this disorder been so hard to crack?

Autism is what we call a mosaic disease, so it has many different facets to it. I discovered that by reading a lot of papers on the subject; about 500 in the last year or so, covering all the different areas of autism research. That’s actually one of the things that most people working in autism don’t tend to do. They work in their own area and they don’t actually look across the whole spectrum. And if you look into the literature, you’ll find that autism isn’t just a sort of neuropsychiatric, behavioural, and social disorder, but it’s also associated with gastrointestinal problems in the majority of children. Maybe 70% of the children at some time or other have quite severe gastrointestinal disturbances. But also, there are problems that have been recorded in cardiovascular systems. They have a raised median diastolic blood pressure. They have an abnormal QRS complex. That’s the actual electrical control of the heart. It looks as though they have some renal kidney transport defects as well. So, it’s a systemic disease, but the most obvious effect is the social and behavioural, and so it tends to be associated with that. But it doesn’t mean to say that the other parts of the system aren’t deeply involved in the mechanism of action, and I think what we have to do now using our modern technology is to take a step back, look at the whole problem as a systemic problem, and see how all the abnormal interactions that are occurring in the different organ systems in the body might impact on brain development and to give us the symptoms of autism, which are becoming all too familiar.

Tell me about the changing gut microbiome, and how that affects us.

So, we’ve evolved with this gut microbe biome, as it’s called, which is this complex community of organisms. Everybody’s different in the world, apparently. You have something like a kilogram of microbes inside you, which is a large amount. Maybe 100 trillion cells. That’s ten times as many cells as the rest of your body. If you want to get some statistics, during your lifetime, the amount of gut microbes you produce is the same weight as five full-grown elephants. And the microbes in your gut are more metabolically and biosynthetically active than the rest of your body. So, they have a giant effect on your metabolism. And we’ve evolved with them, and we’ve evolved not only as a species, but also in relation to our diet. And obviously, since the end of the Second World War, our lifestyles, our diets have changed enormously. And therefore, potentially, our microbes and, certainly, our microbial function has probably changed a lot as well.

What are some of the key factors that have changed the microbiome?

Well, antibiotic use would be a very obvious one. Remember, autism was only recorded as a disease in 1944 by Kanner, which is almost exactly the same time as we started to use antibiotics. And I’m not saying that the first cases were caused by antibiotics. But what I’m saying is that antibiotics, especially when given to children or it babies, are bound to alter the microbial balance in the developing microbiome. Remember, I said that it takes about three years to develop that. When you produce a sudden shockwave through that through an antibiotic, it could derail; it could change the direction of the development. And it’s recently been shown by David Relman in Stanford that once you’ve had antibiotics, the microbes do recover. This is in adults. The microbes do recover but they never go quite back to what they were before the antibiotic therapy. And of course, in children where it’s a developing or a changing microbiome, the effect will be of antibiotics will be amplified over what happens in adults.

And diet. There’s a lot of controversy about how diet interacts with microbes. Microbes have got different dietary preferences. There’s no question about it. They’re all different species. They have different metabolic activities. So, if you change the diet, you’re almost certain to change the balance of power in this complex ecology in your gut. What people are unclear about is whether those changes are permanent or reversible or whatever. However, most people have been looking at it, or most scientists have been looking at it, from the point of view of the composition. Genetically, who’s there; which microbes are present. But microbes respond to the conditions that they’re in, so if you change the diet, even if who’s there doesn’t change much, what they’re doing does change. And that’s the important point from the metabolic point of view, that the microbes could stay exactly the same in terms of the species composition, but what they’re doing in the body and their position in the ecology may change radically. And that’s the effect that the host feels.

So, are we a long way from knowing which of the bacteria are “bad” bacteria?

Well, we know from Sid Finegold’s work that the Clostridial populations are very abnormal. And the Clostridia include a range of bacteria, some of which are very friendly and important for us, and others which are super dangerous, like botulism. You know, botulinus toxin, one of the most toxic substances in the world comes from Clostridia. So, you’ve got a spectrum of hostility, from good really through to bad within the Clostridia, and we know the Clostridial populations are very abnormal. So, the—a smoking gun is lying there at least. But the important thing to remember is that these microbes, it might not be just one species of bacteria; it might be combinations of them and how they work together metabolically, and that’s a much more complicated problem and, quite frankly, I think that’s much more likely to be true than just finding one rogue bug. I think if it was one rogue bug, we’d have probably found that already. So, it’s the combination, the abnormal ecology, and how it interacts with the body which changes development.

High amounts of sulphur have been found in the urine of autistic children. What’s the significance of sulphur depletion in autistic people?

It’s well-known and it’s been known for many years that there are abnormalities in sulfur metabolism in autistic children. There’s evidence that they lose sulfate and other inorganic sulfur components in the urine and in really quite large amounts, which implies a renal transporter defect—which is involved in recovering sulfur from the urine. If you don’t have that working properly, you lose it. That’s potentially a big problem because sulfur is a highly demandable, important commodity in development. It’s required for all sorts of different processes. So, the interesting thing is that there may be a fundamental sulfur problem in autistic children. The microbes that they have, the abnormal microbes, are almost certainly associated with the production of metabolites that require sulfur for further processing. So, if you have this nasty potential combination of a sulfur defect which could be genetic, linked with microbes that demand sulfur, you have a problem of depletion of an essential resource that the body needs to grow and develop, including brain development. That’s only a theory at the moment but it’s something that’s quite interesting: gene-environment idea.

Do you see a diagnostic application for autism coming out of your work looking at disease signatures in urine?

I think there’s several different ways you can apply this technology and approach to studying autism. The first one is, can you diagnose autism earlier than is currently present? At the moment, it’s based on a complex set of behavioural traits and by the time, the diagnosis of autism is first made – which is typically about eighteen months or older – of course, a lot of the damage has been done. So, the real question would be, can we detect things which will show earlier on that there is a problem? And if so, can we do something about it, right? Can we change the interaction, the biochemistry of the body to stop the problem developing? So, there’s two parts. One is early diagnosis because the earlier you try and fix autism, whichever way you use, and behavioural therapy is one of them, the better you can fix it. And children can be cured nearly by behavioural therapy if you intervene very early. So, early diagnostics is a very important, unmet medical need. And the other thing is if we can understand how the metabolism has gone wrong, and it has an environmental cause, can we take that environmental cause away, thus preventing some cases of autism? I’m not sure that we can prevent all because I think there are some genuine cases which are really very, very early and potentially pre-birth, and which will probably have a genetic origin. But we’re really not sure about the proportions of the different types of autism that we observe.

You mentioned that most studies have been on done on children over three years of age. Why is this significant?

It’s very apparent if you start to read the general literature in autism and look at all the different areas of study, whether it’s the behaviour, the treatment, the neurology, the imaging that’s been done, or the biochemistry, all the children that have been looked at pretty much—in the scientific literature, have been over the age of three. Well, the damage occurs before the age of three, by definition, as a matter of fact. So, there are very few studies that have looked at autism in the very early stages of development, which is exactly when you need to look at it if you’re going to understand how it occurs. So, of course, that’s difficult to do because it’s still a comparatively rare disease. So, the way we have to really address that is … It’s actually quite simple; is we need to look at families where they’ve already got an autistic child because the chance of them getting a second autistic child is actually a lot higher than the general population. So, one of the things we could do is to look prospectively at families who already have an autistic child; look at their subsequent infants and try and monitor them through their early stages and see if we can find when they become metabolically or microbiologically abnormal, and see if we can therefore find some predictor of autism. And—and this isn’t just simply a genetic thing, either. It’s trying to identify key dietary changes, key environmental changes which are associated with the onset of autism. So, it needs careful clinical notes linked to metabolic or microbial profiling.

If you could get those resources together to design that study, what do you think the result would be?

I think the result would be we’d be able to identify at least some classes of autism that were preventable, right? We’re trying to raise money to do this sort of study at the moment. And we’re talking about, you know, millions of dollars, so it is an expensive study to do it properly. But if you look at the cost of autism, particularly in the United States, and the projected costs in the future, these are astronomical. So, in 1980, for instance, it was about 1 in 15,000 children that were thought to have autism, right? Current numbers is less than 1 in 100. This is now starting to make it a common childhood disease. And the behavioural therapy that’s given—for instance, in the state of California, is something like $100,000 per year per patient. It is an astronomical cost and if you look at the rate of increase of autism over the last five or ten years, well, it’s not exponential but it’s going up on a steep curve. And if you project that—and it sounds like scaremongering, but if you project those curves ahead 25 or 30 years, you’re looking at potentially an autistic child in every family in America. A trillion dollar problem, okay? So, it may be that the thing will curve off and it won’t be such a big problem. We just don’t know. But at the moment, there is quite a steep rise and it’s huge costs. So, spending a few million dollars, even $10 million, in trying to understand the triggers is trivial in comparison with the health care costs in the future.

2 thoughts on “Prof. Jeremy Nicholson Interview

  1. Great Interview. I have been interested in Mr. Nicholsons work for awhile, as three generations of my family are affected by autism. Thank you for posting this.

  2. Thank you for this program and the interview, it is so refreshing to hear someone speak about autism and actually make sense. Isn’t it a very tragic state of affairs that a scientist who does background reading on autism pathophysiology is an exception rather than the rule!

    I agree with the point Prof Nicholson is making on the need for detailed profiling of ASD patients – in my view this is crucial not only for prevention but also for finding out effective treatments.

    Parents are often faced with the mantra that “there is no firm evidence that Biomedical treatments for autism work.

    True. There is nothing in the published literature, no large placebo-controlled double blind study ever conducted that established beyond doubt that any single biomedical intervention is an effective treatment for autism.

    There will probably NEVER ever be a firm proof that a biomedical treatment (including diets and vitamin supplements) works for autism – not until we can with all certainty define what Autism(s) really is, and what Biomedical intervention really means.

    ‘Autism’ (or ADHD for that matter) is an artificially constructed, descriptive term. Autism has no substance, it does not exist as an entity in itself, but is merely a descriptive term for a collection of observable symptoms (which are variable and can be completely different from child to child). Autism is defined and diagnosed solely by those surface symptoms. There is nothing else to it. Take away the symptoms and this thing-without-substance-called-autism disappears.

    And those symptoms are only surface manifestations of some of body’s biology gone awry.

    Even if we suppose, for the sake of argument, that those body systems are not functioning properly because of faulty genes, there is STILL something dysfunctional on the very basic physiological level that is causing a child to exhibit SYMPTOMS of that thing-with-no substance-called-autism.

    No one has really got a clue on what Autism REALLY is. All that a diagnostic psych ‘expert’ can do is to describe common symptoms (which again will vary greatly) into oblivion. They cannot even start to scratch the surface of what and how causes those symptoms. They will try to tell you that it is all genetic, but again without having a clue about what is going on on the biological, three-dimensional, level.
    So let’s suppose for a moment that all symptoms of autism are caused by faulty genes. The exact pathology will differ greatly from child to child. So for example a great majority of monogenetic SLO syndrome kids exhibit symptoms of autism, but so do most of Timothy Syndrome individuals, and very many PKU kids, and very many Fragile X, most of Retts individuals etc. In those monogenetic disorder individuals their symptoms of autism are not caused by the (dys)functioning of the same gene and not the same downstream pathways (although some of them probably overlap, but that is another long story…), and accordingly we would not attempt to address their autism in the same way!! For example SLOS is a monogenetic disorder of dysregulated cholesterol metabolism and membrane caveolin signalling. The affected children are very sick and great majority of them also have autism (as well as gastrointestinal and immune dysfunction). There is lots anecdotal evidence that SLOS children, when treated with supplemental cholesterol, also lose their autism symptoms. In this case supplemental cholesterol IS their Biomedical Intervention for Autism. (And let’s be reminded, once again, that there is nothing to ANY autism apart from the surface symptoms. The thing is
    without substance or dimension.)

    Timothy Syndrome is a result of a monogenetic mutation affecting calcium trafficking via cell membrane. Great majority of affected individuals also have autism. There is good reason to believe (lots of promising research in this area) that blocking calcium channels might work towards reducing autism symptoms in these cases.
    Now to the point: if we were to design a study to test whether cholesterol supplementation improves symptoms of autism, should we include Timothy syndrome kids alongside SLO kids? Would you also throw some Rett’s and Fragile X kids into the mix? Similarly, if calcium blockers are shown to treat autism in Timothy syndrome individuals, would you automatically assume that it will work the same way for autism in kids with Fragile X?

    There is every reason to believe that ‘idiopathic’ autism is a big mixture of genetic susceptibility to a variety of environmental insults. So the exact pathology will be different in each case… The best we can hope for at the moment is to get a clearer idea of different ‘subgroups’ of autism, and to get clear biomarkers for those subgroups (some will be overlapping and fluctuating, no doubt). Only then it will become possible to design meaningful treatment studies that can ‘prove’ anything beyond doubt.

    Having said that … while there is little we know little about exact pathology and how it differs between individuals, what we DO know is that there is lots and lots that is medically very abnormal in our children. There are plenty of good quality studies providing evidence of a whole-body, systemic disease process in autism, findings such as:
    Generalised immune dysfunction and inflammation including microgliosis and astrogliosis, vascular endothelial inflammation, abnormal vasoconstriction and permeability, reduced blood flow to brain, oxidative stress, systemic glutathione depletion, mitochondrial dysfunction, autoimmune reactivity, mast cell activation, cardiovascular abnormalities, increased intestinal permeability, gut dysbiosis, microbial translocation (presence of bacterial toxins in the blood), hyperplasia of intestinal epithelial cells, pancreatic enzyme deficiency, autonomic/vagal dysfunction, abnormal cytokine profiles, abnormal gene methylation, celebral folate deficiency, increased levels of osteopontin (autoimmune marker that correlates to degree of neurological impairment in neuroimmune diseases such as NeuroAIDS) and so on and on.

    Again these exact pathologies will vary from individual to individual, AND so will the symptoms and severity of autism. Biggest challenge now is to sort them into some kind of groups in order to study interventions.

    The other big problem encountered by anyone wishing to study biomedical interventions for autism is funding and political will. Good quality large scale double blind placebo studies require lots of money and large numbers of participants. Tragically most of grant money goes to psychological and behavioural ‘eye-gaze’ studies (the ones that like to observe surface symptoms into oblivion) and to gene hunt research (which has all to date come back more or less empty handed). Most large institutes, those that can apply and carry out large scale studies, are led by psychiatrist and/or geneticists. Vicious cycle. I know of a researcher who was granted a large amount of money by a US governmental body to study one particular biomedical intervention, only to hit a wall when he approached those big autism institutes, the ones who could round up large numbers of children, large enough for a study to be able to ‘prove’ anything. He already had the money, only needed their cooperation, but they were not interested or organised enough. So his large scale well controlled study is not going to happen. He managed to find a willing institute in another country, but their numbers of children are very small. If you wish to try that biomedical intervention you will have to rely on anecdotal reports and that small scale study that might not mean much when it comes out. The situation is not much different for any other biomedical treatment.

    There was a fantastic article recently on Chronic Fatigue Syndrome/Myalgic Encephalomyelitis by David Tuller, Prof of Journalism and Public Health at Berkeley University (CFS/ME is another ‘mysterious’ disease with no known cause, no ‘proof’ of an underlying biological mechanism and no ‘solid proof’ that it can be treated by biomedical means, which btw shares most of pathological findings with autism).
    Just swap the words CFS with autism below, and you get what I know holds very true for autism, in every way.

    “… once you start paying attention and reading papers, this looks like a chronic or hyper-immune activation. These patients have a lot of signs that their immune systems are firing almost constantly.”

    According to this view, the revved up immune system is actually much less effective at controlling other infections, and studies have found associations between CFS and a grab-bag of pathogens, including members of the herpesvirus, parvovirus, and enterovirus families. Recent research from Norway has also lent support to the hypothesis that at least some people with CFS are suffering from a form of autoimmune disorder, perhaps triggered by one or multiple infections. Neurological impairments are also virtually always part of the complex.

    … In many cases, additional research has failed to confirm associations from prior studies. Yet there is a reasonable epidemiologic explanation for such divergent results: Most experts believe that there are likely many sub-groups or clusters of CFS patients, with a variety of infectious and possibly environmental exposures; studies that don’t account for such distinctions—and most haven’t–are much less likely to reach consistent results about causation or treatment. Moreover, different research groups have used different methods of identifying people with chronic fatigue syndrome, making it even harder to compare findings across studies—a situation that can encourage speculation that the roots of the illness lie in patients’ psyches.
    “This ambiguity over definitions has made it difficult for researchers to pinpoint a biological cause. …”

    (full article by David Tuller can be accessed on http://tinyurl.com/d3ndyqy)

Leave a Reply

Your email address will not be published. Required fields are marked *

You may use these HTML tags and attributes: <a href="" title=""> <abbr title=""> <acronym title=""> <b> <blockquote cite=""> <cite> <code> <del datetime=""> <em> <i> <q cite=""> <strike> <strong>