The Coming Age of Fetal Genomics

It's 2020. A young woman and her partner have just found out that she's pregnant with her first child. and they're going to be parents.

They're overjoyed, of course. But they're also worried. They've seen the adverts warning parents-to-be about the risk of de novo mutations - genetic mistakes that occur inside sperm or egg cells, and affect the child. These mutations, the ads say, are much more common than previously believed and they can cause all kinds of problems: intellectual disabilities, autism, infertility, mental illness, heart malformations - pretty much anything.

The scariest part? Because these are new mutations, out of the blue, they can affect any family. A clear family history is no protection. They don't discriminate by race or lifestyle. It's just the luck of the draw - except that older parents are at much higher risk, especially older fathers. In the case of our couple, she's 28 and he's 32. Perfectly normal for this day and age - but very old in biological terms. Humans evolved to be grandparents by 32, not parents. "The stakes couldn't be higher. Why leave it to chance?"

So they don't. Instead, they buy a $100 test kit, they each provide a small blood sample and send it off to one of the companies offering fetal genome testing. At the testing lab, they can separate out the mother's DNA from that of the fetus, both of which are present in the mother's blood. By comparing the fetal genome to the mother's and father's, it's easy to spot de novo mutations. If a certain gene doesn't match either the mother or the father's sequence, it's mutated.

A few days later the results are back. There are several mismatches detected. Most are benign - they're not predicted to have any biological effects. But there's one, a deletion of a few thousand bases in a gene involved in brain development. This deletion is predicted to raise the risk of epilepsy and autism from 1% to 10% apiece.

The parents now have a decision to make. The mutation is a one off, it's not inherited. If they conceive again... roll the dice again... and it'll be gone. Do they terminate?

Like the adverts say, "Some people disagree with this, but we say there's only one person who really matters: your baby."

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This is likely to become possible in the next few years.

A paper just published in Nature reports on the Non-invasive prenatal measurement of the fetal genome. The technique relies on the fact that the blood of a pregnant woman contains DNA: hers, obviously, but also that of the unborn child. This cell-free DNA can be extracted and genotyped.

This has been possible for a few years, but until now, only fairly crude genetic information could be detected. An extra chromosome, such as in Down syndrome, is pretty easy to spot. This technique is already used to diagnose Down's syndrome and a few other disorders prenatally.

But those diseases are just the low-hanging fruit at the tip of the iceberg, if you see what I mean. To gather the kind of detailed genomic information that could diagnose thousands of disorders is harder: the fetal and maternal genomes are mixed up, and the challenge is to tease them apart. But according to the Stanford geneticists behind the Nature paper, and other teams, it's now possible as early as the first trimester.

What makes the new method so revolutionary is that it is, as the title of the paper says, non-invasive. It's already possible to sequence a fetal genome, but it takes a surgical procedure involving inserting a needle into the womb, and a degree of risk. It's not something you can just sit down and do - but blood samples are. So cell-free DNA will make fetal genomics a personal choice, a commercial product.

The resolution's still not 100%, but inevitably, it will become cheaper, faster and more accurate as technology advances. This year we're expected to see the cost of reading a whole human genome falling below $1000. Fetal genomes will be more expensive, but not enormously so. In 5 or 10 years, it's likely to be affordable.

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What will happen? I think there'll be demand for such services. Most parents won't do it, but enough people will that it will be a major issue. Just look at countries where boys are more valued than girls: a lot of sex-selective abortion happens. Today, it's limited to gender, because it's easier to determine a fetus's sex than its genome. In 5 or 10 years, they'll both be easy.

With demand will come companies to supply these services and, inevitably, advertizing. I doubt these adverts will be on TV, because there will be opposition to the whole idea and boycotts of broadcasters who run them. But we'll be getting spam emails about it. People will worry even over the harmless mutations: a variant won't need to be really associated with a disease, just believed to be, to make people panic.

Socially, it's likely to be divisive. The anti-abortion types will obviously not approve. But it will drive a wedge between those who support abortion but oppose "discriminatory" abortion against the disabled, and those who support the right to terminations 'for any reason, or none'.

Politically, there will be pressure to regulate this, but legally, it'll be tricky. I can't see how you'd prove that any given abortion is motivated by genetic concerns, so unless you ban abortion outright, that won't work. Banning fetal (or all) genomics except under medical supervision might be possible, but people could always go (or send a few drops of blood) abroad to get around that.

I'm not sure where I'll stand on this, but it looks very likely that we'll each have to make a decision in the coming years.

Fan HC, Gu W, Wang J, Blumenfeld YJ, El-Sayed YY, and Quake SR (2012). Non-invasive prenatal measurement of the fetal genome. Nature PMID: 22763444

Why Blogs Fail

I can think of several new neuroscience blogs that started out with some really nice content, but then they disappeared after a few weeks or months. I'm sure the same must be true of other genres. This is a shame.

Thinking back over the early days of Neuroskeptic, my advice to new bloggers is: it gets better. The early days of any blog are psychologically tough because almost inevitably, your first posts are not going to get the recognition they deserve.

That's because people tend to really pour their hearts into early posts - these are the ones that express thoughts you've been mulling over for ages and are finally writing about - and then inevitably, hardly anyone reads them, because it's a new blog and no-one even knows it's there yet. Certainly that was my experience.

Luckily, it doesn't stay that way. Your first posts will flop, at least in relation to your own expectations, but remember that a) it's nothing personal and b) no-one except you cares. Only you can see your traffic stats and whatever, but even if everyone knew them, they wouldn't mind. You need to push on through that stage and once you do, you won't care about it either.

To get past the first stage, you need to "sell" your blog. I think a lot of new bloggers forget this, or think it somehow won't apply to them, which sets them up for disappointment. Of course, good content is essential - no matter how hard you try, you can't sell crap. But great writing alone is not enough. No, not even yours.

Promotion is part of blogging, but once you get into the right mindset, you'll realize that it's not a chore so much as a natural extension of writing. You write something, and then you go and find people who'll be interested in it, and who might have interesting comments about it, and try and get them involved. Or you get involved in conversations about the topics you're interested in.

Sell, don't beg. Outright asking more established people for links, retweets etc. rarely works and it looks bad. Get people interested in it. If that's a chore, then it means you're not really interested in your own stuff, in which case that's a problem.

If you've done this for, say, a year, then I'd say you've given blogging a good shot and you can make an informed decision as to whether or not it's for you. But if you quit after just a couple of months because "I tried blogging and it didn't work out" or "I had a blog but no-one read it" then I'd say you're probably making a mistake. You haven't experienced all of blogging, only the start of it, which is the toughest and least rewarding part. It gets better.

When Data Filtering Introduces Bias

Oh no. Another worrying methods problem for neuroscience, this time for electrophysiologists: Systematic biases in early ERP and ERF components as a result of high-pass filtering.

The event-related potential (ERP) and event-related field (ERF) techniques provide valuable insights into the time course of processes in the brain. Researchers commonly filter the data to increase the signal-to-noise ratio. However, filtering may distort the data, leading to false results. Using our own EEG data, we show that acausal high-pass filtering can generate a systematic bias easily leading to misinterpretations of neural activity... among 185 relevant ERP/ERF publications, 80 used cutoffs above 0.1Hz. As a consequence, part of the ERP/ERF literature may need to be re-analyzed.

The problem in brief: many researchers use a high-pass filter on their electroencephalography (EEG) and magnetoencephalography (MEG) recordings of brain electrical activity. A high-pass filter removes low frequency (i.e. slow) changes from the signal. These slow fluctuations are often considered to be mere "noise".

The problem is that these filters have side effects: as well as 'cleaning up' the data, they can also distort it. There are two main kinds of filter: causal filters are well-known to mutate the signal. Acausal high-pass filters avoid these dramatic artefacts -

But David Acunzo and colleagues point out that acausal filters can actually be more dangerous, because they still distort the data, just in more subtle ways that are harder to spot. In particular, acausal filters can alter the signal at time points before the true signal begins. See the pic above.

That's not necessarily a problem in all cases, but it's certainly bad news for researchers interested in measuring exactly when neural responses happen.

The authors highlight an area of neuroscience where this problem could be misleading researchers. The very earliest brain responses to visual stimuli, about 90 milliseconds after the stimulus onset, is called the "C1" response. Classically, it was thought that the size of the C1 wave was purely a 'bottom-up' phenomenon, determined only by the brightness etc. of the stimulus. But recently, studies have reported 'top down' modulation of C1 by attention, emotional state, etc.

Acunzo et al point out that many of these studies used strong acausal filtering and that what might be happening is that attention actually causes late changes to the visual response, but that due to filtering artefacts, these late changes appear in the data sooner than they really happen. They advise that only weak (low threshold) high-pass filters should be used, and that interesting findings in filtered signals need to be checked against the raw data.

Acunzo DJ, Mackenzie G, and van Rossum MC (2012). Systematic biases in early ERP and ERF components as a result of high-pass filtering. Journal of neuroscience methods PMID: 22743800

Can You Learn To Be Synaesthetic?

A neat study from Dutch psychologists Olympia Colizoli, Jaap Murre and Romke Rouw claims that it's possible to train people to have something a bit like synaesthesia - which they call Pseudo-Synesthesia through Reading Books with Colored Letters.

Synaesthesia generally comes out of the blue - some people just have it while others don't. Those who do experience it typically report that they've always had it. But could it be learned?

Colizoli et al recruited 17 non-synaesthetes and got them to read books specially printed such that 4 common letters, "a", "e", "s" and "t", were always printed in a certain colour: red, orange, green or blue. The idea was that constant exposure to the coloured letters might trigger grapheme-color synaesthesia, which is a relatively common 'naturally occurring' form of the condition.
 
On average each volunteer read 100,000 words of the polychromatic prose. They also got a special browser plug-in to colour internet text in the same way, however, most people didn't use it.

What happened? The subjects experienced a colour-letter Stroop interference effect consistent with the idea that they'd learned particular colour-letter associations, although on another task there was no effect. But what was it actually like, subjectively? The size of the Stroop effect was correlated with self-reported synaesthetic experience on the question "I am experiencing color when thinking about certain letters".

However, the average answer to this question was only 2.5 on a scale from 1 to 5, which doesn't seem very high, and of course there was no control group, so this is hard to interpret. They don't seem to have quizzed people about the subjective experience in much detail, which is a bit of a shame. Six months later, participants could barely remember the letter-color pairs better than guessing.

So to be honest, it's all a bit inconclusive, but it's a cool idea.

Although you might expect the coloured text arrangement to be annoying, many participants said that they quite enjoyed it once they got used to it. Only 2 out of the 17 gave up before finishing a book, while several volunteered to read additional books. So if you want to try and give yourself synaesthesia, it could be doable.

Colizoli O, Murre JM, and Rouw R (2012). Pseudo-Synesthesia through Reading Books with Colored Letters. PloS one, 7 (6) PMID: 22761905

The Racist Brain?

Is the human brain... a racist?

There are some worrying indications that it could be. After all, the cerebrum is largely composed of so-called "white" matter, and the only black area is a little 'ghetto' at the bottom called, shockingly, the substantia nigra...!

Seriously though. There's a paper just out in Nature Neuroscience from Kubota et al that looks at The Neuroscience Of Race. It's a fine review as far as it goes, but to me at least, it really shows up the limits of contemporary neuroscience.

We are told that

A network of interacting brain regions is important in the unintentional, implicit expression of racial attitudes and its control. On the basis of the overlap in the neural circuitry of race, emotion and decision-making, we speculate as to how this emerging research might inform how we recognize and respond to variations in race and its influence on unintended race-based attitudes and decisions.

So there have been studies investigating which bits of American's brains activate in response to looking at photos of black people vs. white people. It emerges that "a network of interacting brain regions" light up. But so what?

Sure, the brain reacts differently to seeing people of different races. Of course it does - it reacts differently to everything, so long as we can perceive a difference; that's how we perceive a difference. And of course race, a deeply emotive issue in American politics and culture, activates 'emotional' parts of the brain - that's how it's emotive.

The included studies all scanned Americans and (presumably) mostly college students. Now most American college students are not active racists, and indeed I'd imagine that their emotional brains are more likely to be worrying self-referentially about racism than about the actual race of the stimuli. No-one seems to have scanned card-carrying members of the KKK. Furthermore, "race" in these studies almost always means "blackness". What about Latinos, Asians?

So what have we learned?

I don't think we've learned much about race. "Race" after all is a confused mixture of emotions, attitudes and beliefs. These differ greatly from person to person, and even the same individual may experience conflicting feelings in different contexts. Kubota et al note this and say that it may explain the mixed findings (black faces activate the amygdala more than white in some studies, not in others) but I'd have said that in this case, only inconsistent results are credible.

What does it tell us about the brain? I'd say not much. The authors weave a neat little narrative - in response to seeing black faces, the amygdala and other emotional areas activate as a negative emotional response; the ACC then detects this racist response and sees that it's unacceptable, and the DLPFC then suppresses it like a parent hurriedly interrupting a young child who's making a faux pas.

But all the elements of this story - the automatic, emotional amygdala, the supervisory DLPFC - are borrowed from other neuroscience studies so at best the race literature confirms these theories but it doesn't even really do that, because there are many other possible interpretations.

I'd say that we need to know much more in terms of the 'basic' neuroscience of emotion, attitudes and beliefs because we can tackle the hornet's nest of race in the brain.

Kubota JT, Banaji MR, and Phelps EA (2012). The neuroscience of race. Nature neuroscience, 15 (7), 940-8 PMID: 22735516