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Will The New DNA Encyclopedia ENCODE Change Our Understanding Of Childhood Disorders?

Thursday, September 27th, 2012

Virtually every developmental, behavioral, and emotional disorder is assumed to have a significant genetic component. Autism, ADHD, depression, anxiety, addiction, dyslexia – you name it, DNA is believed to play a role. For decades, genetic research has sought to uncover the specific genes that contribute risk to all these disorders. While progress has been made – including lots of hints that certain genes may play some role for some disorders – the overall state of the field is that there is much that still needs to be learned about genetics and childhood disorders. The latest hope is that a new understanding of how the human genome may be achieved by a deeper understanding of how DNA really works, as described in more than two dozen papers recently published.

The research initiative called ENCODE is focused on extensive regions in DNA that were thought to be, well, junk. You may have heard that only 20% of DNA is actually doing something. Well the new research is showing that nearly 80% of DNA is doing something, and what’s really important is not just the genes that code for proteins, but also the vast number of genes that act as switches that turn other genes on and off. This regulatory function has been known for a long time, and it’s importance has always been grasped. What’s different now is that it seems to be a predominant mechanism with many genes devoted to it. And researchers believe that it may hold clues to understanding how many disorders arise from expression of genetic risk factors.

What is really changing is the emerging idea that it’s not so much what is in the “core” genes that directly code for things,  but rather the complex mix of influences that turn genes on and off and hence influence development. Here’s where non-genetic influences – ranging from the prenatal environment to parenting strategies – may mechanistically link to how genes get expressed, or not.

You can anticipate sometime in the far, and probably near, future research studies that begin to explore this. There is certainly hope that embracing this increasing complexity of genetic systems will lead to more progress than we’ve seen in the past in terms of deliverables that either explain the causes of disorders or imply potential treatments. That, of course, remains to be seen, as we have heard lots of hype over the decades of how genetics will revolutionize our understanding of childhood disorders. We’ll need to take a wait and see approach to this – and continue to embrace interventions that are known to work right now for disorders, even without knowledge of genetic underpinnings. To that end, let’s hope that research portfolios continue to be diversified and not over-invest in genetic strategies that may, or may not, actually revolutionize treatment.

DNA and RNA via Shutterstock.com 

 

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Dads, DNA, And Choices

Thursday, September 27th, 2012

The scientific paper describing the increases in DNA mutations that correspond to increases in paternal age – published last month (click here to see my discussion of the scientific aspects of the study) – has generated lots of discussion about the need for reconsidering how age may affect paternity and fathering. See, for example, Lisa Belkin’s thoughtful discussion about the utility of men hearing the ticking of a biological clock.

It can be argued that the biological role of fathers, with respect to age, has not received as much attention because we think of the biological clock as primarily representing the probability of being able to reproduce – with those effects being, of course, most pronounced for females. What is now emerging into the public awareness (based on a number of studies conducted over a number of years) is that paternal age – like maternal age – may be associated with an increased risk for passing on certain genetic risk factors that may confer risk for disorders.

We may get to a point where there are risk charts that quantify the increasing probability of paternal mutations that correspond to age and associations with risk for various disorders in offspring (much of the interest right now comes from the potential links between paternal age and autism). Consider, for example, this chart showing the increasing probability of having a child with Down syndrome as predicted by maternal age.

The complexity here is that prospective parents have to consider, in most cases, probabilities rather than certainties (unless there is a screening for a known genetic disorder that runs in a family). Is a 1% chance, versus a .5% or a .01% chance, enough to change someone’s family planning? This is tough to answer. For some people, it may be highly influential. For others, social and personal factors may override such probabilities. What is clear is that genomic research will continue to deliver more and more probabilities in the future (near and far) – and the information that is generated will pertain to both prospective moms and prospective dads. And that prospective parents will have to make more and more complicated choices that are partially (but not fully) informed by genomics.

Statistics and probability via Shutterstock.com

 

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Will There Ever Be A Universal Theory Of Autism?

Friday, August 31st, 2012

This month two ideas about the causes of autism have been put into the spotlight. One idea that has been given some play is that spontaneous mutations – primarily tied to paternal age – are a major etiological factor  that may in fact be a primary reason for the increase in autism over the last few decades. A different idea has also been in the spotlight   – that there are fundamental problems in the immune system which start in the womb which may be responsible for as many as 1 in 3 cases of autism. 

While there is some science to back these claims, their juxtaposition highlights the complexity and confusion of trying to make sense of where we are at in terms of understanding the causes of autism. Over the decades, there have been many grand theories, all of which have needed to be tempered to some degree (and in many cases, to a large degree). What this is may boil down to is that we may never have a universal theory about the cause of autism. Rather, through the lens of history, we may always be wrestling to figure out the degree to which one of two possibilities holds the most traction:

1) It may be that autism is in fact many different disorders which share common features. This is the case, for example, with different types of cancer – while all cancers have some commonality in terms of pathology, they may in fact be thought of as very different diseases, with different causes and potential treatments.

2) It may be that autism is in principle a multifactorial disorder, meaning that there are a number of factors that operate in conjunction to contribute to risk for autism. In this model, there can be a number of genetic loci and environmental influences, all of which add some additional risk for autism.

Of course, these two models are not new – they’ve been around for a long time. And they are not necessarily mutually exclusive. But I am reminded of them each time a new study is released. We typically don’t read much about the bigger picture of autism as the merits of the particular theory and method get discussed. As you continue to follow research in autism, I suggest that you, in your mind, temper the large claims that may come with new avenues of research, until the day comes that we have not only strong evidence supporting it but also translation into effective treatments. Despite all the scientific talent aimed at understanding autism these days, it remains a puzzling disorder or group of disorders. While it would be amazing to have a universal theory that becomes proven and leads to either prevention or eradication, the reality is that slow and steady approaches that fit findings into the bigger puzzle probably offer the most realistic hope for the many ways we will need to understand autism.

Puzzle patterned ribbon symbolizing autism via Shutterstock.com

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Autism And Paternal Age: What’s The Take-Home Message For Parents?

Friday, August 31st, 2012

You may have read recently about a study that links the age of a father with the risk for autism. While there is some real science here to report, there is also the possibility of making too much of all this. So let’s break it down. 

Prior studies have suggested a link between the age of a dad and the risk for autism – as a dad’s age increases, so does the risk. The new study (published in the journal Nature) reports on a possible mechanism for this: it involves the number of genetic mutations that are passed on to a child. Click here to read a summary in the journal.

There are a few underlying ideas that are important. This line of research is showing that genetic mutations are much more frequent in a father’s sperm than in a mother’s egg. This makes sense, in that the sperm are produced throughout the lifespan in men, but women are born with their lifelong supply of egg cells. The authors of the Nature paper suggest that there is a steady increase across decades in a man’s life – so that when you are 40 you will produce more mutations than when you are 30 (and so on).

What’s the connection with autism? Well, right now it is a very indirect association. There is lots of interest in the idea that spontaneous mutations play a role in causing autism. Lots of papers have been published on this over the last few years. So the thinking here is something like connecting the dots – if spontaneous mutations are involved in the etiology of autism, and a dad’s age is a primary source of such mutations, then perhaps there is a link.

All that said, keep in mind the following:

1) The new study published in Nature did not provide any direct association between the mutations and autism

2) The assumption is that many of the mutations are harmless (and in fact somewhat normative)

3) There is, at this point, no clinical screening process to determine or suggest that a father passed on a mutation to a child

4) There are, at this point, no genetic counseling implications

Perhaps most importantly, there are lots of factors that contribute to the etiology of autism. There are certainly heritable factors that go beyond spontaneous mutations. And there are undoubtedly non-genetic factors as well.

So where are we at? At this point, spontaneous mutations are just more potential pieces of the puzzle with respect to the etiology of autism. They will continue to be researched and, hopefully, may in the future reveal more about the underlying biology of the disorder. But it’s way too early to begin to transfer the basic science into diagnostics and prevention – and too early to know what role spontaneous mutations will be shown to play in the broader context of multifactorial influences on autism.

DNA image via Shutterstock.com

 

 

 

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Autism And The Immune System: What’s The Take-Home Message For Parents?

Friday, August 31st, 2012

Last week, an essay was published in the New York Times describing the hypothesis that one of the causes of autism involves a dysfunction in the immune system. In this opinion piece, autism was described as an inflammatory disease that starts during gestation (in the womb). The author speculated that 1 in 3 cases of autism may be due to mechanisms relating to problems with the immune system. 

This line of research is certainly being pursued. Autism Speaks, for example, published a news report in response to the opinion piece, in which they discussed how they have, and continue, to support research that examines the role of the immune system as one of the pathways that may influence the development of autism. That said, they make two very important points:

1) Researchers disagree on the extent to which immune system dysfunction actually is a cause of autism – it may be that the immune system responds to brain and developmental changes that are due to other causes

2) There is currently no evidence that treatments for autism that are rooted in treating an immune system dysfunction are effective – though some are under study

I would add the following:

3) There is no definitive evidence that 1 in 3 cases in autism is due to immune system dysfunction, and as of now there are no diagnostic tests that would screen for this with precision

It’s important that science gets discussed in the popular press, and that parents have an opportunity to become informed on the latest thinking and research. However, opinion pieces – like the one in the New York Times – should (in my own opinion) present a more balanced viewpoint that accurately assesses the landscape (including divergent or more tempered opinions) and the real implications for parents right now. Without that, parents who read these pieces may come away with take-home messages that are not really accurate.

Having a child who has been diagnosed with autism changes a parent’s life. Theories come and theories go – and the realities of the difficulty in elucidating the causes of autism persist. When introducing relatively new ideas into the mainstream, I would hope that authors would exercise more caution with their viewpoints, and understand that, in the end, parents just want to know where things really stand – with more grounding and less hyperbole.

Immune system background via Shutterstock.com

 

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